TW486469B - Novel compounds for inhibiting microsomal triglyceride transfer protein and pharmaceutical compositions containing the same - Google Patents

Novel compounds for inhibiting microsomal triglyceride transfer protein and pharmaceutical compositions containing the same Download PDF

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TW486469B
TW486469B TW085100978A TW85100978A TW486469B TW 486469 B TW486469 B TW 486469B TW 085100978 A TW085100978 A TW 085100978A TW 85100978 A TW85100978 A TW 85100978A TW 486469 B TW486469 B TW 486469B
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Scott Adams Biller
John K Dickson
R Michael Lawrence
David R Magnin
Michael A Poss
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Bristol Myers Squibb Co
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Abstract

Compounds are provided which inhibit microsomal triglyceride transfer protein and thus are useful for lowering serum lipids and treating atherosclerosis and related diseases. The compounds have the structure wherein R1 to R6, Q, and X are as defined herein.

Description

486469 經濟部中央標準局員工消費合作社印製 A7 ___B7_ 五、發明説明（i ) 本發明係關於可抑制微粒體三酸甘油酯轉換蛋白質之 新穎化合物，及使用此化合物以降低血清脂肪及治療動脈 粥瘤硬化之方法。 微粒體三酸甘油酯轉換蛋白質（MTP )可催化小草 層泡（SUV)間之三酸甘油酯（TG)，膽固醇酯（ C E )，及磷脂醯膽鹼（P C )之輸送，Wetterau &486469 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___B7_ V. Description of the Invention (i) The present invention is a novel compound that can inhibit microsomal triglyceride conversion protein, and use this compound to reduce serum fat and treat atherosclerosis Method of tumor hardening. Microsomal triglyceride conversion protein (MTP) can catalyze the transport of triglycerides (TG), cholesterol esters (CE), and phospholipids choline (PC) between small grass laminae (SUV), Wetterau &

Zilversmit, Chem. Phvs. Lipids 38· 205-22 (1985)。 當轉換速率係以每份時間所轉換之給予體脂肪百分比表示 時，MTP顯現對中性脂肪輸送（TG及CE)之喜好甚 於對磷脂之輸送。來自牛肝之蛋白質業已離析出及特徵化 ° Wetterau & Z i lversmit, Chem. Phvs. Lipids 38· 205-22 (1985)。純化蛋白質經聚丙烯醯胺膠電泳（ P A G E )分析後顯示，轉換蛋白質爲具有表現分子量爲 58，000及88，000之兩個亞單位之複合物，然 而當純化MT P於未變性狀況下進行電泳時僅存在單一帶 ，而當於十二烷基硫酸鈉（SD S )上進行電泳時，則可 鑑定出具有58，000及88，000兩個表現分子量 之帶。這兩個多肽其後分別稱之爲5 8 kD a及8 8 Dka，或分別稱之爲MTP之58kDa及88kDa 組份，或分別稱之爲MTP之低分子量亞單位及高分子量 亞單位。 將牛MTP之5 8，0 0 0分子量組份特徵化後顯示 ，其爲先前已特徵化之多功能蛋白質，蛋白質二硫化物異 構體酶（P D I )。Wetterau e t a 1. . J. Biol. Chem (請先閲讀背面之注意事項再填寫本頁) ··裝 _ 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 一 4 - (- 6 64 48 A7 __ B7 五、發明説明（2 ) (請先閱讀背面之注意事項再填寫本頁) 2 6.1, T8 00-7 (1990)。轉換蛋白質中P D I之存在可藉由 下列所顯現之證據來支持，亦即（1 )牛MTP之 5 8，0 0 0 kD a組份之胺基終端之2 5個胺基酸與牛 P D I者相同，及（2 )二硫化物異構體酶活性係以5 8 kDa-88kDa，蛋白質複合物離解後之牛MTP表 示。此外，對抗牛PD I之抗體（此蛋白質本身並無TG 轉換活性）可使由含純化牛ΜTP之溶液中所得之牛TG 轉換活性產生免疫沈澱。 _ P D I —般係用來使內漿網狀體之管腔內新合成之二 硫鍵結性蛋白質皺疊及組集。Bulleid & F reeman, N^t.U.r.e 3^., 64 9 -651 (1988)。其催化使半胱胺酸殘基適 當配對成二硫鍵，故催化二硫鍵結性蛋白質之適當皺疊。 此外，P D I亦已述及與人類脯胺醯4 -羥基化酶之石亞 單位相同，Koivu e t a 1. · J. Biol. Chei 2 6 2· 6447-9 經濟部中央標準局員工消費合作社印製 .(1987)。PD I於牛轉換蛋白質中之角色並不清楚。藉低 濃度之變性劑（氫氯酸胍），chaotropic劑（高氯酸鈉） 或非變性去垢劑（辛基葡萄糖苷）使PD I由牛MTP之 8 8 kD a組份中離解後將導致轉換活性之喪失，故 P D I似乎爲轉換蛋白質之主要組份。Wetterau et al·. Biochemistry 2JL 9728-35 (1991)。離析出之牛 P D I 並無明顯之脂肪轉換活性，故不是8 8 k D a多肽爲轉換 蛋白質，就是其給予蛋白質複合物轉換活性。 MT P活性於鼠體內之組織及細胞下分佈業已加以研 究。Weiterau & Zilversmit, Biochem. Biophvs. Acta 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ c; _ _ λ 486469 A7 B7 五、發明説明（3 ) 8 7 5. 61 0 - 7 ( 1 9 8 6 )。脂肪轉換活性已於肝及腸中發現。 (請先閲讀背面之注意事項再填寫本頁) 血漿，腦，心臟或腎內則僅具些微或並無轉換活性。在肝 內方面，MTP爲座落在微粒體部分之管腔內之可溶性蛋 白質。於平滑及粗糙微粒體中所發現之濃度約略相同。 万脂蛋白血缺乏症爲一種正染色體隱性疾病，其特徵 爲血漿中實質上缺乏含有阿樸脂蛋白B (a ρ ο B、）之脂 蛋白。Kane & Havel 於The Metabolic Basis of Inherited Disease· Sixth edition, 1139-64 (1989) 0 血漿之三酸甘油酯（T G )濃度可能低達數毫克/分升， 且難以因攝食脂肪而上升。血漿膽固醇濃度通常僅2 0 -4 5毫克/分升。這些異常係由於肝內極低密度脂蛋白（ V L D L )及腸內乳糜小滴之組集及/或分泌產生遺傳缺 陷之結果。此缺陷之分子基礎在之前尙未測知。所檢查之 病患中，三酸甘油脂，磷脂，及膽固醇之合成呈現正常。 屍體解剖則發現病患並無動脈粥瘤硬化。Schaefer d al.. Clin. Chem. 34· B9-12 (1988)。 a p ο B基因與 經濟部中央標準局員工消費合作社印製 点脂蛋白血缺乏症之間之關聯已爲某些家族所排除。 Talmud et a 1 . · J. Clin. Invest· 82. 180 3-6 ( 1 9 88 ) 及 Huang et a 1. · Am. J. Hum. Genet· 4 6· 1141-8 (1990)。 沒脂蛋白血缺乏症之病患乃受許多病痛所苦。Kane & Havel，同上。病患之腸細胞及肝細胞內之脂肪吸收不良 且造成三酸甘油酯累積。由於富含三酸甘油酯之血漿脂蛋 白之缺乏，故脂溶性維生素諸如維生素E之輸送產生缺陷 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 0 _ 486469 A7 B7____ 五、發明説明（4 ) 。此將'導致紅血球之棘狀細胞過多，脊髓與小腦之失調’ (請先閱讀背面之注意事項再填寫本頁) 以及楔狀束及薄束變性，周邊腎病，變性色素視網膜病變 ，及蠟樣肌病。iS脂蛋白血缺乏症病患之治療包括脂肪攝 取之飮食限制及維生素A，E及K之飮食補充。 於試管試驗內，MTP可催化磷脂膜間脂肪分子之運 送。假定其於活體內扮演類似角色，故於脂肪代謝中有所 用途。MT P在細胞下（微粒體部分之管腔）及組織分佈 (肝及腸）所得之推論爲，其在血漿脂蛋白之組集中有所 用途，此乃因彼等爲血漿脂蛋白之組集位置所致。 We1;1:eraii & Zi lversmit, Biochem. B i ooh v s . Acta 8 7 5, 610-7 (1986)。MTP催化三酸甘油酯於膜間運送之能力 乃與此假設相符，由此可知MTP可催化將三酸甘油酯由 其於內漿網狀體（E R)膜內之合成位運送至內漿網狀體 管腔內之初生脂蛋白微粒。Zilversmit, Chem. Phvs. Lipids 38 · 205-22 (1985). When the conversion rate is expressed as the percentage of body fat administered converted per serving, MTP appears to prefer neutral fat delivery (TG and CE) over delivery of phospholipids. Protein from beef liver has been isolated and characterized. Wetterau & Ziversmit, Chem. Phvs. Lipids 38 · 205-22 (1985). The analysis of the purified protein by polyacrylamide gel electrophoresis (PAGE) showed that the converted protein was a complex having two subunits with molecular weights of 58,000 and 88,000, but when the purified MTP was performed in an undenatured condition There is only a single band during electrophoresis. When electrophoresis is performed on sodium lauryl sulfate (SD S), two bands with molecular weights of 58,000 and 88,000 can be identified. These two peptides are hereinafter referred to as 58 kDa and 88 Dka, respectively, or the 58 kDa and 88 kDa components of MTP, or the low molecular weight and high molecular weight subunits of MTP, respectively. Characterization of the 58,000 molecular weight component of bovine MTP showed that it was a previously characterized multifunctional protein, protein disulfide isomerase (P D I). Wetterau eta 1.. J. Biol. Chem (Please read the notes on the back before filling out this page) ··· _ The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm)-4-(- 6 64 48 A7 __ B7 V. Description of the invention (2) (Please read the notes on the back before filling out this page) 2 6.1, T8 00-7 (1990). The existence of PDI in converted proteins can be shown by the following Evidence to support, that is, (1) the 5, 8 0 0 0 kD component of the bovine MTP a 25 amino acids are the same as those of bovine PDI, and (2) disulfide isomerase The activity is expressed as 5 8 kDa-88 kDa, the bovine MTP after the protein complex is dissociated. In addition, the anti-bovine PD I antibody (the protein itself does not have TG conversion activity) enables the bovine obtained from the solution containing purified bovine MTP TG conversion activity produces immunoprecipitation. _ PDI —Generally used to fold and assemble the newly synthesized disulfide-bonded proteins in the lumen of the endoplasmic reticulum. Bulleid & Freeman, N ^ tUre 3 ^ ., 64 9 -651 (1988). It catalyzes the proper pairing of cysteine residues into disulfide bonds, so it catalyzes disulfide bondability. Appropriate wrinkling of white matter. In addition, PDI has also been described as the same as the stone subunit of human Proline 醯 4-hydroxylase, Koivu eta 1. · J. Biol. Chei 2 6 2 · 6447-9 Central Standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives. (1987). The role of PD I in bovine conversion proteins is unclear. By low concentration of denaturant (guanidine hydrochloride), chaotropic agent (sodium perchlorate) or non-denaturing detergent Agent (octyl glucoside) dissociates PDI from the 88 kD a component of bovine MTP and results in loss of conversion activity, so PDI appears to be the main component of the conversion protein. Wetterau et al .. Biochemistry 2JL 9728- 35 (1991). The isolated bovine PDI has no obvious fat-converting activity, so either the 88 k D a peptide is a conversion protein or it is a protein complex-converting activity. MT P activity is in the tissues and cells of the mouse. Distribution has been studied. Weiterau & Zilversmit, Biochem. Biophvs. Acta This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) _ c; _ _ λ 486469 A7 B7 V. Description of the invention (3) 8 7 5. 61 0-7 (1 9 8 6). Fat conversion activity has been found in the liver and intestines. (Please read the precautions on the back before filling out this page.) Plasma, brain, heart or kidney are only slightly or inactive. In the liver, MTP is a soluble protein located in the lumen of the microsomal portion. The concentrations found in the smooth and rough microsomes were approximately the same. Apolipoproteinemia is a recessive orthochromosome disease characterized by a substantial lack of lipoproteins containing apoprotein B (a ρ ο B,) in plasma. Kane & Havel in The Metabolic Basis of Inherited Disease · Sixth edition, 1139-64 (1989) 0 Plasma triglyceride (T G) concentrations may be as low as several milligrams per deciliter, and it is difficult to rise due to ingestion of fat. Plasma cholesterol concentration is usually only 20-4 5 mg / dL. These abnormalities are the result of genetic defects due to the assembly and / or secretion of very low density lipoprotein (VL D L) in the liver and chyle droplets in the intestine. The molecular basis of this defect has not been known before. In the patients examined, the synthesis of triglycerides, phospholipids, and cholesterol appeared normal. Autopsy revealed no atherosclerosis. Schaefer d al .. Clin. Chem. 34 · B9-12 (1988). The association between a p ο B gene and dot lipoproteinemia deficiency printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs has been excluded in some families. Talmud et a 1. J. Clin. Invest 82. 180 3-6 (1 9 88) and Huang et a 1. Am. J. Hum. Genet 4 6 1141-8 (1990). Patients with apoproteinemia are suffering from many diseases. Kane & Havel, ibid. The patient's intestinal cells and liver cells have poor malabsorption of fats and cause triglyceride accumulation. Due to the lack of triglyceride-rich plasma lipoproteins, the transport of fat-soluble vitamins, such as vitamin E, is defective. The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 0 _ 486469 A7 B7____ V. Invention description (4). This will 'cause too many spinous cells of red blood cells, imbalance of spinal cord and cerebellum' (please read the precautions on the back before filling out this page), and wedge and thin bundle degeneration, peripheral kidney disease, degenerative pigmented retinopathy, and waxy Myopathy. Treatment for patients with iS lipoproteinemia deficiency includes dietary restrictions on fat intake and dietary supplementation of vitamins A, E, and K. In a test tube test, MTP catalyzes the transport of fat molecules between phospholipid membranes. It is assumed that it plays a similar role in the living body, so it is useful in fat metabolism. The inference of MT P under the cells (lumen of the microsomal part) and tissue distribution (liver and intestine) is that it is useful in the plasma lipoprotein group because they are the plasma lipoprotein group Location. We1; 1: eraii & Zi lversmit, Biochem. B i ooh v s. Acta 8 7 5, 610-7 (1986). The ability of MTP to catalyze the transport of triglycerides between membranes is consistent with this hypothesis. It can be seen that MTP can catalyze the transport of triglycerides from their synthesis sites in the endoplasmic reticulum (ER) membrane to the endoplasmic network. Primary lipoprotein particles in the lumen of the body.

Oloffson及colleagues業已研究H e p G 2細胞內之 脂蛋白組集作用。β〇s t r〇m e t a 1 . , J . Biol. Chem . 263 經濟部中央標準局員工消費合作社印製 ,4434-42 ( 1 9 88 )。其結果指出小先質脂蛋白乃隨時間而 變大。此乃與當彼等組集時，脂肪分子乃添加至或轉換至 初生脂蛋白中之現象相符β MT P可能於此過程中有所用 途。欲支持此假設，Howel 1 and Palade, J. Cell Biol. 92，833-45 ( 1 982 )乃將初生脂蛋白由鼠肝之肝高爾基部 分中離析出。所存在之微粒大小乃隨脂肪及蛋白質組份之 不同而不同。其發現含有apoB之高密度脂蛋白（ H D L )微粒。Higgins and Hutson, J. L i p i d Res 25 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X297公釐）—7 一 — 486469 A7 ____B7___ 五、發明説明（5 ) ,1 2 9 5M 3 0 5 (1984)，指出由高爾基中離析出之脂蛋白乃 一致地大於由內漿網狀體中離析出者，同樣地可知脂蛋白 之組集爲進行性。 最近之報告（3(^611。6,¥〇 1.25 8,0 9 9 9，1 9 9 2;〇· S h a r p e t a 1 · , N a t u r e, V ο 1. 3 6 5 , p 6 5 , 1 9 9 3 證實導致 点脂蛋白血缺乏症之缺陷乃在M TP基因內，故而於 MTP蛋白質內。石脂蛋白血缺乏症之個體由於MTP基 因之突變而不具Μ T P活性，某些業已特徵化r這些結果 指出，MTP爲合成含apoB之脂蛋白，諸如VLDL (LDL之先質）所需。因此，MTP抑制劑可抑制 VL D L及L D L之合成，故而可降低動物及人類之 VLDL值，LDL值，膽固醇值，及三酸甘油酯值。 1994年3月2日公布之加拿大專利申請書第 2，091 ，102號（相當於1993年9月3曰公布 之美國專利申請書系列第1 1 7，3 6 2號（file DC2 lb ))報告MTP抑制劑，其亦可阻斷人類肝細胞系（ 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁)Oloffson and colleges have studied the role of lipoprotein aggregation in He p G 2 cells. β〇s t r0me e t a 1., J. Biol. Chem. 263 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, 4434-42 (19 88). As a result, it was pointed out that the small progesterone lipoprotein became larger with time. This is consistent with the fact that fat molecules are added to or converted into nascent lipoproteins when they are assembled. Β MT P may be useful in this process. To support this hypothesis, Howel 1 and Palade, J. Cell Biol. 92, 833-45 (1 982) isolated primary lipoproteins from the Golgi part of the liver of rats. The particle size varies depending on the fat and protein components. It was found to contain high density lipoprotein (HDL) particles of apoB. Higgins and Hutson, J. L ipid Res 25 This paper size is applicable to China National Standard (CNS) A4 (210 X297 mm) — 7 — — 486469 A7 ____B7___ 5. Description of the invention (5), 1 2 9 5M 3 0 5 (1984) pointed out that lipoproteins isolated from Golgi were consistently larger than those isolated from endoplasmic reticulum. Similarly, the group of lipoproteins was known to be progressive. Recent reports (3 (^ 611.6, ¥ 〇1.25 8, 0 9 9 9, 1 9 9 2; 〇 Sharpeta 1 ·, N ature, V ο 1. 3 6 5, p 6 5, 1 9 9 3 It was confirmed that the defect causing the lipoproteinemia deficiency is in the M TP gene, and therefore in the MTP protein. Individuals with lithioproteinemia lack MTP activity due to mutations in the MTP gene, and some have been characterized by r These results indicate that MTP is required for the synthesis of apoB-containing lipoproteins, such as VLDL (precursor of LDL). Therefore, MTP inhibitors can inhibit the synthesis of VL DL and LDL, and thus can reduce the VLDL value and LDL value of animals and humans , Cholesterol value, and triglyceride value. Canadian Patent Application No. 2,091,102 issued on March 2, 1994 (equivalent to US Patent Application Series No. 1 1 published on September 3, 1993 , 3 6 2 (file DC2 lb)) reports MTP inhibitors, which can also block human liver cell lines (printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page)

HepG2細胞）中含apoB之脂蛋白之製造。其更進 一步支持了 MTP抑制劑於活體內可降低含a ρ ο B之脂 蛋白及脂肪濃度之說法。此加拿大專利申請書揭示鑑定 MTP抑制劑之方法HepG2 cells) production of apoB-containing lipoproteins. It further supports the claim that MTP inhibitors can reduce the concentration of lipoproteins and fats containing a ρ ο B in vivo. This Canadian patent application discloses a method for identifying MTP inhibitors

本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 486469 A 7 B7 五、發明説明（6 ) 其名爲^·2 -〔 1 一（3，3 -二苯基丙基）一 4 —哌啶基 〕_2，3 -二氫基一 3 -合氧基—1 1L 一異蚓跺氫氯酸 鹽及This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 486469 A 7 B7 V. Description of the invention (6) Its name is ^ · 2-[1- (3,3-diphenylpropyl) ) A 4-piperidinyl] _2,3-dihydro- 3 -synthoxy-1 1L isopropylammonium hydrochloride and

其名爲1 一〔3 -（6 -氣!基—1—某滿基）甲基〕—4 一〇一甲氧基苯基哌嗪 本發明係提供作爲Μ 丁 Ρ抑制劑之新穎化合物，其具 有下列之結構 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製Its name is 1- [3- (6-Ga! -L-l-methyl) methyl] -4-10-methoxyphenylpiperazine. The present invention provides novel compounds that are inhibitors of butyl benzene, It has the following structure (please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

或 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 9 - 486469 槪 8· ! ? Α7 _Β7_ 五、發明說明（7 ) ’ 〇 〇Or This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 9-486469 槪 8 ·!? Α7 _Β7_ V. Description of the invention (7) ′ 〇 〇 〇

II II 其中Q爲一 c —或一 s —;II II where Q is a c —or a s —;

II 〇 X 爲：CHR8，一 C —，— CH— CH —或II 〇 X is: CHR8, a C —, — CH — CH — or

II II II 〇 R 9 R 10 -c = c -； i 9 R 1 0 118，119及111°分別爲氫，烷基，烯基，炔基，芳基，芳 烷基，雜芳基，雜芳烷基，環烷基，或環烷基烷基； R1爲下列結構之芴基型基團 --------------裳--- (請先閱讀背面之注意事項再Wk本頁) 訂：II II II OR 9 R 10 -c = c-; i 9 R 1 0 118, 119 and 111 ° are hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, hetero Aralkyl, cycloalkyl, or cycloalkylalkyl; R1 is a fluorenyl group of the following structure -------------- Shang --- (Please read the note on the back first Matters on this page again)

經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

R1爲下列結構之芘基型基團 丨線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 486469 A7 B7 五、發明説明（8 )R1 is a fluorene-based group of the following structure 丨 line · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 486469 A7 B7 V. Description of the invention (8)

(a=2,3或 4(a = 2, 3 or 4

13 或13 or

R 或R or

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

Z1及Z2乃相同或互異且各爲一個鍵，0，S s • I 〇 (〇)2 NH- C— II 0 烷基 C— II 0 C- II Ο Η 或—？一 0Η 經濟部中央標準局員工消費合作社印製 ) 惟有關i方面，Ζ1及Ζ2中至少有一者不爲一個鍵； R11爲一個鍵，烷撐，烯撐或炔撐（最多爲1 0個碳 原子），芳撐（例如 "Ο" 或混合型芳撐-烷撐（例如 其中η爲1至6 ; R12爲氫，烷基，烯基，芳基，鹵烷基，三鹵烷基 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X 297公釐）_ ^ 486469 A7 _^B7_ 五、發明説明（9 ) 三鹵烷基烷基，雜芳基，雜芳基烷基，芳烷基，芳烯基， 環烷基，芳氧基，烷氧基’芳烷氧基或環院基烷基，惟（ 1 )當R12爲Η，芳氧基，烷氧基或芳烷氧基時，則Z2 爲一ΝΗ — C —，一 Ν -C —，一 C 一或一個鍵；且（Z1 and Z2 are the same or different and each is a bond, 0, S s • I 〇 (〇) 2 NH- C—II 0 alkyl C—II 0 C-II 〇 Η or —? 10Η Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs) However, with regard to i, at least one of Z1 and Z2 is not a bond; R11 is a bond, alkylene, alkenylene, or alkynylene (up to 10 carbons) Atom), arylene (such as " 〇 " or mixed arylene-alkylene (such as where η is 1 to 6; R12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, etc.) Standards apply to China National Standard (CNS) A4 specifications (210X 297 mm) _ 486469 A7 _ ^ B7_ V. Description of the invention (9) Trihaloalkylalkyl, heteroaryl, heteroarylalkyl, aralkyl , Arylalkenyl, cycloalkyl, aryloxy, alkoxy 'aralkyloxy or cycloalkylalkyl, except (1) when R12 is fluorene, aryloxy, alkoxy or aralkyloxy , Then Z2 is one N—C—, one N—C—, one C one or one bond; and (

II II II 〇 烷基 〇 〇 2 )當Ζ2爲一個鍵時，則R1 2不可爲雜芳基或雜芳基烷 » Ζ爲一個鍵，0，S，N —烷基，Ν -芳基，或具1 至5個碳原子之烷撐或烯撐； R13，R1 4，R15及R16乃各自爲氫，烷基，鹵基， 鹵烷基，芳基，環烷基，環雜烷基，烯基，炔基，羥基， 烷氧基，硝基，胺基，硫基，烷磺醯，芳磺醯，烷硫基， 芳硫基，胺羰基，烷羰氧基，芳羰胺基，烷羰胺基，芳烷 基，雜芳基，雜芳基烷基，或芳氧基； R15 a及Rie a乃各自爲R15及R16中之任一者，惟羥 '产. 基，硝基，胺基或硫基除外。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) R 2 ，R3 ，R4乃各自爲氫，鹵基，烷基，烯基， 烷氧基，芳氧基，芳基，芳烷基，烷巯基，芳毓基，環烷 基，環烷基烷基，雜芳基，雜芳基烷基，羥基或鹵烷基； R5爲烷基，烯基，炔基，芳基，烷氧基，芳氧基， 芳烷氧基，雜芳基，芳烷基，雜芳基烷基，環烷基，環雜 烷基，雜芳氧基，環烷基烷基，聚環烷基，聚環烷基烷基 ，環烯基，環烯基烷基，聚環烯基，聚環烯基烷基，雜芳 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 486469 A7 B7 五、發明説明（ίο ) (請先閲讀背面之注意事項再填寫本頁) 羰基，1胺基，烷胺基，芳胺基，雜芳胺基，環烷氧基，環 烷胺基’所有R5取代基及R6取代基（下文所示）均可 經由可利用之碳原子而被1 ，2，3或4個由氫，鹵基， 院基’鹵院基’垸氧基，_院氧基，矯基，块基，環院基 ，環烷基烷基，環雜烷基，環雜烷基烷基，芳基，雜芳基 ，芳烷基，芳環烷基，芳烯基，芳炔基，芳氧基，芳氧基 烷基’芳烷氧基，芳偶氮基，雜芳合氧基，雜芳基烷基， 雜芳基烯基，雜芳氧基，羥基，硝基，氰基，胺基，經取 代胺基（其中胺基包括1或2個取代基，其包括烷基，芳 基或雜芳基’或定義中所所述之其它芳基化合物），硫赶 ，燒硫基，芳硫基，雜芳硫基，芳硫基烷基，烷羰基，芳 鐵基’芳胺羰基，烷氧羰基，胺羰基，炔胺羰基，烷胺羰 基’烯胺羰基，烷羰氧基，芳羰氧基，烷羰胺基，芳羰胺 基，芳亞磺醯，芳亞磺醯烷基，芳磺醯，烷磺醯，芳磺醯 胺基’雜芳羰胺基，雜芳亞磺醯，雜芳硫基，雜芳磺醯或 院亞礎酸中所擇定之取代基所取代；此基團最好包括鄰位 疏水取代基諸如烷基，鹵烷基（最多爲5個鹵基團），烷 經濟部中央標準局員工消費合作社印製 氧基’鹵烷氧基（最多爲5個鹵基團），芳基，芳氧基或 芳烷基； R 爲氨或Ci 一 c4院基或c：t— c<t儲基； 一· —-——............................................... , 乃相同或互異，其各自由含5 一或6 一環節之雜芳基中所 本紙張尺度適用中國國家標準（CNS)A4規格（210 ><297公釐）一 ^ _ 486469 五、發明説明（11 擇定广且 包括式I , 即 Π及Π i化合物之N—氧化物，亦II II II 〇 alkyl 〇 2) When Z2 is a bond, then R1 2 cannot be heteroaryl or heteroarylalkane »Z is a bond, 0, S, N-alkyl, N-aryl, Or alkylene or alkylene having 1 to 5 carbon atoms; R13, R1 4, R15 and R16 are each hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, Alkenyl, alkynyl, hydroxy, alkoxy, nitro, amine, thio, alkanesulfonium, arylsulfonium, alkylthio, arylthio, aminecarbonyl, alkcarbonyloxy, arylcarbonylamino, Alkylcarbonylamino, aralkyl, heteroaryl, heteroarylalkyl, or aryloxy; R15 a and Rie a are each one of R15 and R16, except for the hydroxyl group. Except for amine or thio. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) R 2, R 3, and R 4 are each hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy , Aryl, aralkyl, alkylthio, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; R5 is alkyl, alkenyl, alkyne Aryl, aryl, alkoxy, aryloxy, aralkoxy, heteroaryl, aralkyl, heteroarylalkyl, cycloalkyl, cycloheteroalkyl, heteroaryloxy, cycloalkylalkane Base, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroaromatic This paper is applicable to Chinese National Standard (CNS) A4 specifications ( 210X297 mm) _ 486469 A7 B7 V. Description of the Invention (ίο) (Please read the notes on the back before filling out this page) Carbonyl, 1amino, alkylamino, arylamino, heteroarylamine, cycloalkoxy Cycloalkylamino 'All R5 substituents and R6 substituents (shown below) can be substituted by hydrogen, halo, or phenyl via available carbon atoms Halogenated alkoxy, fluorenyloxy, ammonium, block, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, aralkyl Aryl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl 'aralkoxy, arylazo, heteroaryloxy, heteroarylalkyl, heteroaryl Alkenyl, heteroaryloxy, hydroxyl, nitro, cyano, amine, substituted amine (where amine includes 1 or 2 substituents, which includes alkyl, aryl or heteroaryl 'or in the definition Other aryl compounds mentioned), sulfur, thiosulfanyl, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylferroyl'arylaminecarbonyl, alkoxycarbonyl, aminecarbonyl, Alkylaminecarbonyl, Alkylaminocarbonyl'enaminecarbonyl, Alkylcarbonyloxy, Arylcarbonyloxy, Alkylcarbonylamino, Arylcarbonylamino, Arylenesulfenyl, Arylenesulfonylalkyl, Arylenesulfonyl, Aranesulfonyl醯, arylsulfonylamino'heteroarylcarbonylamino, heteroarylsulfinylsulfonium, heteroarylthio, heteroarylsulfinylsulfonium or basal acid selected by a substituent; this group preferably includes Hydrophobic substituents such as alkanes , Haloalkyl (up to 5 halo groups), alkoxy'haloalkoxy (up to 5 halo groups) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics, aryl, aryloxy or aromatic Alkyl; R is ammonia or Ci-c4 radical or c: t-c < t storage base;----... .........., are the same or different, each of which is derived from a heteroaryl group containing a 5 or 6 link The paper size applies the Chinese National Standard (CNS) A4 specification (210 > < 297 mm) 1 ^ 486469 V. Description of the invention (11) It is widely selected and includes formula I, which is the N-oxide of compounds of Π and Π i ,also

Kj< 及 製藥學上可接受性鹽諸如鹼金屬鹽諸如鋰，鈉 zh金屬鹽諸如鈣或鎂，以及鋅或銀及其它陽離子 諸如銨，膽鹼，二乙醇胺，乙撐二胺，特丁胺，特辛胺， ’以及製藥學上可接受性陰離子性諸如氯離子 ’/臭離子’碗離子，酒石酸鹽，乙酸鹽，甲烷磺酸鹽，馬 》3¾¾酸鹽’戊二酸鹽及天生胺基酸諸如精胺酸， 賴胺酸，丙胺酸.等之鹽，及其前藥酯。 & ’本發明式I及Π化合物包含下列結構之化合物 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐）_ Μ 486469 A7 B7 五、發明説明（12 ) 經濟部中央標準局員工消費合作社印製Kj < and pharmaceutically acceptable salts such as alkali metal salts such as lithium, sodium zh metal salts such as calcium or magnesium, and zinc or silver and other cations such as ammonium, choline, diethanolamine, ethylenediamine, tert-butylamine Tetoctylamine, and pharmaceutically acceptable anions such as chloride ion / odorous ion, tartrate, acetate, methane sulfonate, MA 3¾¾, glutarate, and natural amine Salts of basic acids such as arginine, lysine, alanine, etc., and their prodrug esters. & 'The compounds of the formula I and Π of the present invention include compounds of the following structure (please read the precautions on the back before filling this page) Printed on the paper by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The Chinese National Standard (CNS) A4 specification (210 X 297 mm) _ 486469 A7 B7 V. Description of the invention (12) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(請先閲讀背面之注意事項再填寫本頁) •I裝·(Please read the notes on the back before filling out this page) • I pack ·

、1T 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 486469 A7 B7 五、發明説明（13 ) 經濟部中央標準局員工消費合作社印製、 1T This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) _ 486469 A7 B7 V. Description of invention (13) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(請先閲讀背面之注意事項再填寫本頁) -•I裝· 訂 本紙張尺度適用中國國家標準（〇奶）八4規格（210><297公釐）-16 486469 經濟部中央標準局員工消費合作社印製 A7 ΒΊ_ 五、發明説明（14 ) 此外，本發明亦提供預防，抑制或治療動脈粥瘤硬化 ，胰臟炎或肥胖症之方法，其中，上述式I ，I i ，Π， Π i化合物.係以可降低微粒體三酸甘油酯轉換蛋白質之活 性之量投服。 此外，本發明亦提供降低血清脂肪值，膽固醇及/或 三酸甘油酯，或抑制及/或治療高脂血症，高脂肪血症， 高膽固醇血症，及/或高三酸甘油酯血症之方法，其中上 述式I ，I i ，Π，E i化合物係以可降低微粒體三酸甘 油酯轉換蛋白質之活性之量投服。 除非另有特殊限定，否則下列定義乃應用在本專利申 請書所用之稱謂上。 所謂>MTP 〃乃意指多肽或蛋白質複合物，其（1 )如係由有機體（例如牛，人類）中獲得，則可申均化組 織之微粒體部分中離析出；及（2 )刺激將合成磷脂泡， 膜或脂蛋白中之三酸甘油酯，膽固醇酯或磷脂輸送至合成 泡，膜或脂蛋白中，其乃不同於具有類似催化性質之膽固 醇酯轉換蛋白質〔Drayna e t a 1 · · Nature 3 2 7· 632-6 34 (1 9 8 9 )〕。然而，本發明之Μ T P分子不必具有催化活性 。例如，不具催化活性之Μ T P或其片段可有用以引發對 抗蛋白質之抗體。 本專利申請書中所謂使動脈粥瘤硬化’安定化〃乃意 指使新動脈粥瘤損傷之發展變慢及/或使其形成受到抑制 〇 本專利申請書中所謂|導致動脈粥瘤硬化之消退〃乃 本紙張尺度適用中國國家標準（€奶）八4規格（210/297公釐）_17_ (請先閲讀背面之注意事項再填寫本頁) 486469 A7 —__B7_ ___ 五、發明説明（15 ) 意指降牴及/或消除動脈粥瘤硬化損傷。 (請先閲讀背面之注意事項再填寫本頁) 除非另有指定，否則本文中單獨使用或作爲另一基團 一部份之所謂〜低級烷基"，、烷基"或乃包 括在正鏈中含1至4 0個碳，最好1至2 0個碳，尤其1 至1 2個碳之直及支鏈烴，諸如甲基，乙基，丙基，異丙 基，丁基，特丁基，異丁基，戊基，己基，異己基，庚基 ，4，4 一二甲基戊基，辛基，2 ，2 ，4 一三甲基戊基 ，壬基，癸基，十一基，十二基，其各種不同支鏈異構體 ’以及包含1至4個取代基之此些基團，取代基乃諸如鹵 基，例如，F，Br ，CJ?或I或CF3 ，烷氧基，芳基 ，芳氧基，芳基（芳基）或二芳基，芳烷基，芳烷氧基， 烯基，環烷基，環烷基烷基，環烷基烷氧基，胺基，羥基 ，醯基，雜芳基，雜芳氧基，雜芳基烷基，雜芳基烷氧基 ，芳氧基烷基，芳氧基芳基，烷基醯胺基，烷醯基胺基， 芳羰胺基，硝基，氰基，硫赶，鹵烷基，三鹵烷基及/或 烷硫基，以及供R 5.及R 6定義用之任何其它取代基。 經濟部中央標準局員工消費合作社印製 除非另有指定，否則本文單獨使用或作爲另一基團一 部分之所謂$環烷基"乃包括含有1至3個環之飽和或部 分未飽和（含1或2個雙鍵）之環狀烴基團，其包括含總 共3至2 0個碳以形成環，最好4至1 2個碳以形成環之 單環烷基，雙環烷基及三環烷基且其可稠合成如同供芳基 所述之1或2個芳族環，其包括環丙基，環丁基’環戊基 ，環己基，環庚基，環辛基’環癸基及環十二基’環己烯 基， 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X 297公釐）-18 - i - 46 6 48 A7 B7 經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 五、發明説明（16 ) 1 ί 任何之此些基團可任被1至 諸如鹵素，烷基，烷氧基， ，環烷基，烷基醯胺基，烷 羰胺基，胺基，硝基，氰基 R5或Re定義用之任何其 本文中單獨使用或作爲 基"乃意指含5至2 0個碳 個雙鍵之環狀烴。環烯基團 基，環庚烯基，環辛烯基， 其可如同供環烷基所定義地 本文中單獨使用或作爲 烷基'乃意指含5至2 0個 12個碳及1或2個橋之橋 包括〔3.3.0〕一二環 1〕一二環庚基，〔2.2 同供環烷基所定義地任經取 本文中單獨使用或作爲 烯基"乃意指含5至2 0個 個雙鍵，最好含6至1 2個 基團，聚環烯基之實例包括 ，〔2·2·1〕一二環庚 A . 00 . | 4個取代基所取代，取代基乃 羥基，芳基，芳氧基，芳院基 酿基胺基，合氧基，酸基，芳 ’硫赶及/或院硫基，以及供 它取代基。 另一基團一部分之所謂、環燦 ’最好6至12個碳及1或2 之實例包括環戊烯基，環己烯 環己二烯基，及環庚二烯基， 任經取代。 另一基團一部分之所謂a聚環 碳且含0至3個橋，最好6至 連多環基團。聚環烷基之實例 辛基，金剛烷基，〔2.2· • 2〕一二環辛基等，其可如 代。 另一基團^一部分之所謂 聚環 碳且含0至3個橋及含1或2 碳且含1或2個橋之橋連多環 〔3.3.0〕一二環辛烯基 烯基，〔2·2·2〕一二環 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-19 - 4^6469 經濟部中央標隼局員工消費合作杜印製 A7 B7 _五、發明説明（17 ) 辛烯基等，其可如同供環烷基所定義地任經取代。 本文中單獨使用或作爲另一基團一部分之所謂★芳基 ，或、A r"乃意指在環部分（諸如苯基或棻基）中含6 至10個碳原子之單環或二環芳族基團’其可任包括一至 三個稠合至A r上之其它環（諸如芳基，環烷基，雜芳基 或環雜烷基環）且可任經由可利用之碳原子而被1 ’ 2 ’ 3或4個基團所取代，取代基係由氫，鹵基，鹵烷基，烷 基，鹵烷基，烷氧基，鹵烷氧基，烯基，三氟甲基，三氟 甲氧基，炔基，環烷基烷基，環雜烷基，環雜烷基烷基’ 芳基，雜芳基，芳烷基，芳氧基，芳氧基烷基，芳烷氧基 ，芳硫基，芳偶氮基，雜芳基烷基，雜芳基烯基，雜芳基 雜芳基，雜芳氧基，羥基，硝基，氰基，胺基，經取代胺 基（其中胺基包括1或2個取代基，取代基爲烷基，芳基 或定義中所述之其它芳基化合物），硫赶，烷硫基，芳硫 基、雜芳硫基，芳硫基烷基，烷氧基芳硫基，烷羰基，芳 羰基，烷胺羰基，芳胺羰基，烷氧羰基，胺羰基，烷羰氧 基，芳羰氧基，烷羰胺基，芳羰胺基，芳亞磺醯，芳亞磺 醯烷基，芳磺醯胺基或芳磺醯胺基羰基，或供上述R5或 R6基團所定義之任何取代基中所擇定。 本文中單獨使用或作爲另一基團一部分之所謂％芳烷 基"，a芳基-烷基'或$芳基低級烷基>乃意指具有芳 基取代基之上述烷基團，諸如笮基或苯乙基，或棻丙基， 或上述之芳基。 本文單獨使用或作爲另一基團一部分之所謂a低級烷 本紙張尺度適用中國國家標準（CNS)A4規格（210X297公釐）一 2〇 - ' (請先閱讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（18 ) 氧基〃‘，a烷氧基"，a芳氧基'或a芳烷氧基'乃包括 鍵結至氧原子上之任何上述烷基，芳烷基或芳基團。 (請先閲讀背面之注意事項再填寫本頁) 本文單獨使用或作爲另一基團一部分之所謂A胺基# 可任被一或二個取代基諸如烷基及/或芳基所取代。 本文中單獨使用或作爲另一基團一部分之所謂a低級 烷硫基"， >烷硫基'， >芳硫基"或>芳烷硫基"乃包 括鍵結至硫原子上之任何上述烷基，芳烷基或芳基團。 本文中單獨使用或作爲另一基鼠一部分之所謂a低級 烷胺基〃，〜烷胺基〃，〜芳胺基'或〜芳烷胺基"乃包 括鍵結至氮原子上之任何上述烷基，芳基或芳烷基團。 本文中本身使用或作爲另一基團一部分之所謂$醯基 〇 "乃意指鍵結至羰基團（II )上之有機基團’醯基團 c 之實例包括烷醯基，烯醯基，芳醯基，芳烷醯基’雜芳醯 基，環烷醯基等。. 經濟部中央標準局員工消費合作社印製 本文中單獨使用或作爲另一基團一部分之所謂a烷醯 基〃乃意指鍵結至羰基團上之烷基。 除非另有指定，否則本文中本身使用或作爲另一基團 一部分之所謂％低級烯基〃或 >烯基〃乃意指在正鏈中具 2至20個碳，最好3至12個碳，尤其1至8個碳且在 正鍵中包括一至六個雙鍵之直或支鏈基團’諸如乙烯基’ 2 -丙烯基，3 -丁烯基，2 -丁烯基，4 —戊烯基’ 3 一戊烯基，2 -己烯基，3 -己烯基，2_庚烯基，3 — 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-21 一 486469 A7 ____B7_ 五、發明説明（19 ) 庚烯基' 4 一庚烯基，3 -辛烯基，3 -壬烯基，4 一癸 烯基’ 3--[--碳烯基，4--h二碳嫌基，4，8，1 2 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 一十四碳三烯基等，其可任被1至4個取代基，亦即鹵素 ，鹵烷基，烷基，烷氧基，烯基，炔基，芳基，芳烷基， 環烷基，胺基，羰基，雜芳基，環雜烷基，烷醯基胺基， 烷基醯胺基，芳羰胺基，硝基，氰基，硫赶及/或烷硫基 ’以及供R5或R6定義所用之任何其它取代基所取代^ 除非另有指定，否則本文中本身使甩或作爲另一基團 一部分之所謂 >低級炔基'或★炔基'乃意指在正鏈中具 2至20個碳，最好2至12個碳，尤其2至8個碳且在 正鏈中包括一個三鍵之直或支鏈基團，諸如2 -丙炔基， 3 -丁炔基，2 -丁炔基，4 一戊炔基，3 -戊炔基，2 一己炔基，3 -己炔基，2 —庚炔基，3 —庚炔基，4 一 庚炔基，3 -辛炔基，3 -壬炔基，4 一癸炔基，3 -十 一碳炔基，4 一十二碳快基等，其可任彼1至4個取代基 ，亦即，鹵素，鹵烷基，烷基，烷氧基，烯基，炔基，芳 基，芳烷基，環烷基，胺基，雜芳基，環雜烷基，羥基， 烷醯基胺基，烷基醯胺基，芳羰胺基，硝基，氰基，硫赶 ，及/或烷硫基，以及供R5或Re定義所用之任何其它 取代基所取代。 本文中單獨使用或作爲另一基團一部分（其亦包涵以 a烷基#作爲另一基團之一部分諸如芳烷基或雜芳烷基等 )之所謂a烷撐'乃意指具有單鍵以供在兩個不同碳原子 上與其它基團接合之上述烷基團，其可任被上述供烷基所 t ( CNS ) ( 210X297^ )-22- 486469 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（20 ) 用之取1代基所取代。烷撐之定義乃應用在官能基彼此鍵結 之烷基團上，諸如芳烷基取代基。 本文中單獨使用或作爲另一基團一部分（其亦包涵以 、烯基"或、炔基〃作爲另一基團一部分諸如芳烯基或芳 炔基等）之所謂、烯撐"及、炔撐〃乃分別意指具有單鍵 以供在兩個不同碳原子上接合之上述燦基團及炔基團。 本文中所定義之適當烷撐，烯撐或炔撐基團或 (CH2) „或（CH2) p (其包括烷撐，烯撐或炔撐基團 )可任包括1 ，2或3個烷基，烷氧基，芳基，雜芳基， 環雜烷基，嫌基，炔基，合氧基，芳氧基，羥基，鹵素取 代基以及供R5或Re定義用之任何取代基，此外，鏈中 之一個碳原子可被氧原子，N - Η，N—院基或n -芳基 所替代。烷撐，烯撐，炔撐，（〇112)11及（（：112)13之 實例包括 —CH =CH —CH2 一， —CH2CH =CH 一， —C SC —CH2 —, 一 CH2—· — CH2—CH2—CH2—· o o —ch2cscch2— , —C =CH —ch2—* —(CH2)2 一, —(CH2)3 一， —(CH2)4 一, 一 (CH2>2 —C —CH2CH2 —, —CH々H —，一 CH2CHCH2 —， in, ^ i2H5 —CHCH2 一，— CHCH2CH2 一，— CHCHCHj ·—,(Please read the precautions on the reverse side before filling out this page)-• I Pack · The size of the paper is applicable to the Chinese National Standard (〇 奶) 8 4 specifications (210 > < 297 mm) -16 486469 Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperative A7 ΒΊ_ 5. Description of the invention (14) In addition, the present invention also provides a method for preventing, inhibiting or treating atherosclerosis, pancreatitis or obesity, wherein the above formula I, I i, Π, Πi compounds. Are administered in an amount that reduces the activity of microsomal triglyceride-converting protein. In addition, the present invention also provides for lowering serum fat value, cholesterol and / or triglycerides, or inhibiting and / or treating hyperlipidemia, hyperlipidemia, hypercholesterolemia, and / or hypertriglyceridemia. A method in which the above-mentioned compounds of the formulae I, I i, Π, E i are administered in an amount that reduces the activity of the microsomal triglyceride conversion protein. Unless otherwise specified, the following definitions apply to the titles used in this patent application. The so-called > MTP 〃 means a polypeptide or protein complex, (1) if it is obtained from an organism (e.g. cattle, human), it can be isolated from the microsomal part of the homogenized tissue; and (2) stimulation Delivery of triglycerides, cholesterol esters or phospholipids in synthetic phospholipid vesicles, membranes or lipoproteins to synthetic vesicles, membranes or lipoproteins is different from cholesterol ester conversion proteins with similar catalytic properties [Drayna eta 1 · · Nature 3 2 7 · 632-6 34 (1 9 8 9)]. However, the M T P molecules of the invention need not be catalytically active. For example, mtp or fragments thereof that are not catalytically active can be useful to elicit antibodies to anti-proteins. The so-called "stabilization of atherosclerosis" in this patent application means that the development of new atheroma lesions is slowed and / or its formation is suppressed. The so-called in this patent application | leads to the regression of atherosclerosis 〃It is the size of this paper that applies the Chinese national standard (milk) 8 4 specifications (210/297 mm) _17_ (Please read the precautions on the back before filling this page) 486469 A7 —__ B7_ ___ V. Description of the invention (15) Refers to lowering ridges and / or eliminating atherosclerotic damage. (Please read the notes on the back before filling out this page) Unless otherwise specified, the so-called ~ lower alkyl ", alkyl ", used alone or as part of another group in this article, or included in 1 to 40 carbons in the normal chain, preferably 1 to 20 carbons, especially straight and branched hydrocarbons of 1 to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl , Tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl , Undecyl, dodecyl, its various branched isomers' and these groups containing 1 to 4 substituents, such as halo, for example, F, Br, CJ? Or I or CF3, alkoxy, aryl, aryloxy, aryl (aryl) or diaryl, aralkyl, aralkoxy, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkane Oxy, amine, hydroxy, fluorenyl, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl, aryloxyaryl, alkylamino , Alkylamino, arylcarbonylamino, Group, cyano, thiol, haloalkyl, trihaloalkyl and / or alkylthio, as well as for R 5. R 6, and with the definition of any other substituent. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Unless otherwise specified, the so-called "$ cycloalkyl" used alone or as part of another group includes saturated or partially unsaturated (including 1 to 3 rings) 1 or 2 double bonds) cyclic hydrocarbon groups, including monocyclic alkyl groups, bicyclic alkyl groups and tricyclic groups containing a total of 3 to 20 carbons to form a ring, preferably 4 to 12 carbons to form a ring Alkyl and it can be fused to 1 or 2 aromatic rings as described for aryl, including cyclopropyl, cyclobutyl'cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl 'cyclodecyl And cyclododecyl 'cyclohexenyl, this paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) -18-i-46 6 48 A7 B7 (Please read the notes on the back before filling out this page) V. Description of the invention (16) 1 ί Any of these groups can be assigned to 1 such as halogen, alkyl, alkoxy, cycloalkyl, alkyl Any of amino, alkylcarbonyl, amine, nitro, cyano R5 or Re is used herein alone or as defined herein. Group " is the mean having 5 to 20 carbon double bonds of the cyclic hydrocarbon. Cycloalkenyl, cycloheptenyl, cyclooctenyl, which may be used alone or as alkyl herein as defined for cycloalkyl, means 5 to 20 12 carbons and 1 or The bridges of the 2 bridges include [3.3.0] a bicyclic 1] a bicycloheptyl, [2.2 is defined as a cycloalkyl group and may be used alone or as an alkenyl group in this document " means 5 To 20 double bonds, preferably 6 to 12 groups. Examples of polycycloalkenyl groups include [2 · 2 · 1] -bicycloheptyl A. 00. | 4 substituents, Substituents are hydroxy, aryl, aryloxy, arylamino, amino, oxy, acid, aryl'thio and / or thio, and substituents for it. Examples of the so-called, cyclocan ', preferably 6 to 12 carbons and 1 or 2 which are part of another group include cyclopentenyl, cyclohexene, cyclohexadienyl, and cycloheptadienyl, all of which are substituted. The so-called a-polycyclic carbon which is part of another group and contains 0 to 3 bridges, preferably 6 to even polycyclic groups. Examples of polycycloalkyl are octyl, adamantyl, [2.2 · • 2] -bicyclooctyl, and the like, which may be substituted. The so-called polycyclic carbon of a part of another group ^ containing 0 to 3 bridges and a bridged polycyclic [3.3.0] -bicyclooctenyl alkenyl group containing 1 or 2 carbons and 1 or 2 bridges, [2 · 2 · 2] The paper size of the first and second ring is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -19-4 ^ 6469 Employees' cooperation cooperation with the Central Bureau of Standards, Ministry of Economic Affairs, printed A7 B7 _V. DESCRIPTION OF THE INVENTION (17) Octenyl and the like may be optionally substituted as defined for a cycloalkyl group. The so-called ★ aryl group used alone or as part of another group herein, or A " means a monocyclic or bicyclic ring having 6 to 10 carbon atoms in a ring moiety such as a phenyl or fluorenyl group Aromatic groups' may optionally include one to three other rings (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) fused to Ar and may optionally be via available carbon atoms Substituted by 1 '2' 3 or 4 groups, the substituents are hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl , Trifluoromethoxy, alkynyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl 'aryl, heteroaryl, aralkyl, aryloxy, aryloxyalkyl, aryl Alkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, amine, substituted Amine group (where amine group includes 1 or 2 substituents, the substituent is alkyl, aryl or other aryl compounds as defined in the definition), sulfur, alkylthio, arylthio, heteroarylthio, Arylthioalkyl , Alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminecarbonyl, arylaminecarbonyl, alkoxycarbonyl, aminecarbonyl, alkoxycarbonyl, arylcarbonyloxy, alkaminocarbonyl, arylcarbonylamino, aryl Sulfinsulfonium, arylenesulfonylalkyl, arylenesulfonamido or arylsulfonamidocarbonyl, or any of the substituents defined above for R5 or R6 groups. The so-called% aralkyl ", a aryl-alkyl 'or $ aryl lower alkyl " used alone or as part of another group means the above-mentioned alkyl group having an aryl substituent, Such as fluorenyl or phenethyl, or fluorenyl, or the above-mentioned aryl. This paper uses a so-called a lower alkyl paper alone or as part of another group. The paper size applies to Chinese National Standard (CNS) A4 (210X297 mm)-20- '(Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (18) Oxyfluorene ', a alkoxy ", a aryloxy' or a aralkyloxy 'includes any of the above-mentioned alkyl, aralkyl groups bonded to an oxygen atom. Group or aryl group. (Please read the notes on the back before filling this page) The so-called A amine group # used alone or as part of another group may be substituted with one or two substituents such as alkyl and / or aryl. The so-called a-lower alkylthio ", > alkylthio ', > arylthio " or < aralkylthio " used alone or as part of another group includes bonding to sulfur Any of the above alkyl, aralkyl or aryl groups on an atom. The so-called "lower alkylamino", "alkylamino", ~ arylamino "or" aralkylamino ", used alone or as part of another radical, includes any of the above-mentioned bonds to a nitrogen atom. Alkyl, aryl or aralkyl groups. The so-called $ fluorenyl group used by itself or as part of another group herein means an organic group 'fluorenyl group c bonded to a carbonyl group (II). Examples include alkylfluorenyl, alkenyl , Arylfluorenyl, aralkylfluorenyl 'heteroarylfluorenyl, cycloalkylfluorenyl and the like. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics. The so-called a-alkanoyl group, which is used alone or as part of another group, means an alkyl group bonded to a carbonyl group. Unless otherwise specified, the term "lower alkenyl fluorene" or "alkenyl fluorene" used by itself or as part of another group herein means 2 to 20 carbons, preferably 3 to 12 carbons in the normal chain. Carbon, especially 1 to 8 carbons and straight or branched groups including one to six double bonds in the positive bond 'such as vinyl' 2-propenyl, 3-butenyl, 2-butenyl, 4 — Pentenyl '3 pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3 — This paper size applies to China National Standard (CNS) A4 (210X297 mm) -21 486469 A7 ____B7_ V. Description of the invention (19) Heptenyl '4 -heptenyl, 3-octenyl, 3-nonenyl, 4 dedecenyl' 3-[-alkenyl, 4- -h 2-Carbonyl, 4, 8, 1 2 (Please read the notes on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed 14 carbon trienyl, etc., which can be used by 1 Up to 4 substituents, namely halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, amine, carbonyl, heteroaryl, cycloheteroalkane Alkyl Substituted by amine, arylcarbonylamino, nitro, cyano, thio, and / or alkylthio 'and any other substituents used for the definition of R5 or R6. Unless otherwise specified, this document itself refers to Or so-called " lower alkynyl " or ★ alkynyl 'as part of another group means having 2 to 20 carbons in the normal chain, preferably 2 to 12 carbons, especially 2 to 8 carbons and in the The normal chain includes a straight or branched group with a triple bond, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl , 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decylynyl, 3-undecynyl , 4,12 carbons, etc., which can be any one to four substituents, that is, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, aralkyl, Cycloalkyl, amine, heteroaryl, cycloheteroalkyl, hydroxy, alkylamino, alkylamido, arylcarbonylamino, nitro, cyano, thio, and / or alkylthio , And any other substituents used for the definition of R5 or Re. The so-called a-alkylene 'used alone or as part of another group (which also includes a alkyl # as part of another group such as aralkyl or heteroaralkyl, etc.) means having a single bond The above-mentioned alkyl group for joining with other groups on two different carbon atoms can be used by the above-mentioned alkyl group (CNS) (210X297 ^) -22-486469 Preparation A7 B7 V. Description of the invention (20) Replace it with a 1-generation group. The definition of alkylene is applied to alkyl groups where functional groups are bonded to each other, such as aralkyl substituents. The so-called, alkenyl, used alone or as part of another group (which also includes, alkenyl " or, alkynyl fluorene as part of another group such as aralkenyl or aralkynyl, etc.) and The alkynylene group means the above-mentioned bright group and alkynyl group having a single bond for joining on two different carbon atoms, respectively. Suitable alkylene, alkenylene or alkynylene groups or (CH2) or (CH2) p (which includes alkylene, alkenylene or alkynylene groups) as defined herein may optionally include 1, 2 or 3 alkanes , Alkoxy, aryl, heteroaryl, cycloheteroalkyl, alkynyl, alkynyl, alkoxy, aryloxy, hydroxy, halogen substituents and any substituents used for the definition of R5 or Re, in addition One of the carbon atoms in the chain can be replaced by an oxygen atom, N-fluorene, N-phenyl or n-aryl. Alkylene, alkenylene, alkynylene, (〇112) 11 and ((: 112) 13 of Examples include —CH = CH —CH2 one, —CH2CH = CH one, —C SC —CH2 —, one CH2 — · — CH2 —CH2 —CH2 — · oo —ch2cscch2—, —C = CH —ch2— * — ( CH2) 2 one, — (CH2) 3 one, — (CH2) 4 one, one (CH2 > 2 —C —CH2CH2 —, —CH々H —, one CH2CHCH2 —, in, ^ i2H5 —CHCH2 one, — CHCH2CH2 One, — CHCHCHj · —,

CH3 CiHs I ch3 本紙張尺度適用中國國家標隼（ CNS)A4規格（2l〇X297公釐）一 23 - (請先閱讀背面之注意事項再填寫本頁) :裝· 訂 486469 A7 B7 五、發明説明（21 0 0 II 0 II II -CH2CH2〇-C- -· · -ch2ch2n-c— H ,-ch2ch2- n— C一 t ch3 一 ch2_ ch3 -c —CH2 一 ,一 (CH2)5 F 1 一，一(CH2)2 -C — CH2 -1 1 ch3 F Cl ch3 ch3 —ch2- 1 -CH 一 CH2— •， 一(CHa)2 — •CH— , — CH2 — CH— C— ch3 ch3 —ch2 · —CH - -CH _ 1 _CH2 一， _ •CH2 一CH 一CH2 一CH -， 1 1 1 ch3 ch3 ch3 ch3 0H —CH —CH2CH2 —OCH2CH2-— -(ch2)3一cFa-" 〇CH3 -CH-CH2CH2 CH2OCH5— # CH2NHCH2—， 一 NHCH2CH2—， —· N— CH2CH2 — » » ch3 ch3 ch3 I • ch2_n — ch2 (請先閲讀背面之注意事項再填寫本頁) (ch2)； • ch2- • (CHj) 2 — C— CHj— I ch3 CH3 (CH 山一c—CHa- ,-(CH2>3· ch3 I ch3 或 ch3 % I (CH2 ) 3 —· C- 經濟部中央標準局員工消費合作社印製 本文中單獨使用或作爲另一基團一部分之所謂5_素 ，或、鹵基〃乃意指氯，溴，氟及碘，以及（：1?3 ，以氯 及氟較理想。 所謂A金屬離子"乃意指鹼余屬離子諸如鈉’鉀或鋰 等，以及鹼土金屬離子諸如鎂及鈣等’以及鋅及鋁。 本文中單獨使用或作爲另一基團一部分之所謂A環雜 烷基"乃意指包含1至2個雜原子諸如氮，氧及/或硫， 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-24- 486469 A7 _____B7 _五、發明説明（22 ) 且經由"碳原子或雜原子，如可能的話，經由鍵結劑 (CH2) p (其乃如上所述）鍵結之5 —，6 -或7 —節 飽和或部分未飽和環，諸如o. (Y. a ：0-，0—，CH3 CiHs I ch3 This paper size is applicable to China National Standard (CNS) A4 (21 × 297 mm)-23-(Please read the precautions on the back before filling this page): Binding · Order 486469 A7 B7 V. Invention Explanation (21 0 0 II 0 II II -CH2CH2〇-C--·· -ch2ch2n-c— H, -ch2ch2- n— C—t ch3—ch2_ ch3 -c —CH2 one, one (CH2) 5 F 1 One, one (CH2) 2 -C — CH2 -1 1 ch3 F Cl ch3 ch3 —ch2- 1 -CH one CH2— •, one (CHa) 2 — • CH—, — CH2 — CH— C— ch3 ch3 — ch2 · —CH--CH _ 1 _CH2 One, _ • CH2-CH-CH2-CH-, 1 1 1 ch3 ch3 ch3 ch3 0H —CH —CH2CH2 —OCH2CH2-—-(ch2) 3-cFa- " 〇 CH3 -CH-CH2CH2 CH2OCH5— # CH2NHCH2—, NHCH2CH2—, — · N— CH2CH2 — »» ch3 ch3 ch3 I • ch2_n — ch2 (Please read the notes on the back before filling this page) (ch2); • ch2 -• (CHj) 2 — C— CHj— I ch3 CH3 (CH Shanyi c—CHa-,-(CH2 > 3 · ch3 I ch3 or ch3% I (CH2) 3 — · C- Employees of the Central Bureau of Standards, Ministry of Economic Affairs Consumer cooperatives print this article separately The so-called 5-sulfonate or halofluorene used or as part of another group means chlorine, bromine, fluorine and iodine, and (: 1 to 3, chlorine and fluorine are preferred. The so-called A metal ion " Means alkali residual ions such as sodium 'potassium or lithium, etc., and alkaline earth metal ions such as magnesium and calcium, etc.' and zinc and aluminum. The so-called A-ring heteroalkyl " used alone or as part of another group herein It means that it contains 1 or 2 heteroatoms such as nitrogen, oxygen and / or sulfur. The size of this paper applies to China National Standard (CNS) A4 (210X297 mm) -24-486469 A7 _____B7 _V. Description of the invention (22) And via a " carbon atom or a heteroatom, if possible via a bond (CH2) p (which is as described above), of a 5-, 6-, or 7-section saturated or partially unsaturated ring, such as o . (Y. a: 0-, 0-,

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 等。上述基團可包括1至3個取代基諸如上述Ri，R5或 R6基團之任一者。此外，任何之上述環可稠合至1或2 個環烷基，芳基，雜芳基或環雜烷基環上》 本文中單獨使用或作爲另一基團一部分之所謂〜雜芳 基#或 或 (亦稱爲雜芳基）乃意指包括1 ，2，3或4個雜原子諸 如氮，氧或硫等之5 -或6 -節芳族環，此環乃稠合至芳 基，環烷基，雜芳基或環雜烷基環（例如苯並_吩基，口引 跺基）上，且係經由碳原子或雜原子，如可能的話，經由 鍵結劑（C Η 2 ) p (其乃如上所述）鍵結，諸如 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 25 - 486469 A7 B7 五、發明説明（23 ) 猶，(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, etc. The aforementioned group may include any of 1 to 3 substituents such as the aforementioned Ri, R5 or R6 groups. In addition, any of the above rings may be fused to 1 or 2 cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl rings. As used herein alone or as part of another group, the so-called ~ heteroaryl group # Or or (also known as heteroaryl) means a 5- or 6-membered aromatic ring comprising 1, 2, 3 or 4 heteroatoms such as nitrogen, oxygen or sulfur, which ring is fused to an aryl group, On a cycloalkyl, heteroaryl or cycloheteroalkyl ring (eg, benzo-phenyl, fluorenyl) and via a carbon or heteroatom, if possible via a bonding agent (C Η 2) p (which is as described above) bond, such as this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)-25-486469 A7 B7 V. Description of the invention (23)

OH^/〇 K^/s fS ，U , U , 等，且包括所有可能之N -氧化物衍生物。OH ^ / 〇 K ^ / s fS, U, U, etc., and includes all possible N-oxide derivatives.

V, V 或 V 乃相同或互異，其乃如同上文所述’且係於鄰近位置（亦 即鄰位或1 ，2 —位）接合至菇基或芴基型基團之中央環 上β此基團之實例包括 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標隼（CNS)A4規格（ 210X297公釐）_ 26 _ 486469 A7 B7 五、發明説明（24 )V, V, or V are the same or different, as described above, and are connected to the central ring of a mushroom-based or fluorenyl-type group at an adjacent position (that is, ortho or 1, 2-position). β Examples of this group include (please read the notes on the back before filling out this page) Printed on the paper by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 26 _ 486469 A7 B7 V. Description of the invention (24)

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 其中u係由0，S乃NR 中所擇定； R7a爲Η，低級烷基，芳基，—C (0) R7b， 一 C (〇）〇 R 7b ; R 7b爲烷基或芳基，且包括所有可能之N -氧化物衍生物 〇 包括上述基團之雜芳基團可任包含1至4個取代基， 諸如陳列供芳基所用之任何取代基，或指定供R 5或R 6 基團用之彼些取代基。此外，任何上述之環可稠合至環烷 基，芳基，雜芳基或環雜烷基環上。 本紙張尺度適用中國國家標準（CNS )A4規格（ 210X297公釐）-27 一 486469 A7 __B7_ 五、發明説明（25 ) 本汝中單獨使用或作爲另一基團一部分之所謂-環雜 烷基烷基'乃意指經由碳原子或雜原子鍵結至（C H2) p 鍵上之上述環雜烷基團。 本文中單獨使用或作爲另一基團一部分之所謂a雜芳 基烷基"或a雜芳基烯基"乃意指經由碳原子或雜原子鍵 結至上述一（CH2)。鏈，烷撐或烯撐上之上述雜芳基團 〇 本文中所謂’芴基'或’芴基類似物/ .或二芴基型基 團π乃意指下列結構之基團： (請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, where u is selected from 0, S is selected from NR; R7a is Η, lower alkyl, aryl, -C (0) R7b, -C (〇) 〇7b; R7b is an alkyl or aryl group, and includes all possible N-oxide derivatives. Heteroaryl groups including the above-mentioned groups may optionally contain 1 to 4 Substituents, such as any substituents listed for use with aryl groups, or some substituents designated for use with R 5 or R 6 groups. In addition, any of the above rings may be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -27 a 486469 A7 __B7_ V. Description of the invention (25) The so-called -cycloheteroalkylalkane used alone or as part of another group in this book The group 'means the above-mentioned cycloheteroalkyl group bonded to a (C H2) p bond via a carbon atom or a heteroatom. The so-called "a heteroarylalkyl group" or "a heteroarylalkenyl group" used alone or as part of another group herein means a bond to the above-mentioned one (CH2) via a carbon atom or a heteroatom. The above-mentioned heteroaryl group on a chain, alkylene or alkenylene. The so-called 'fluorenyl' or 'fluorenyl analogue /. Or a difluorenyl group π herein means a group of the following structure: (please first (Read the notes on the back and fill out this page)

經濟部中央標準局員工消費合作社印製 本文中所謂Α茹基型基團〃乃意指下列結構之基團： 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 28 - 486469 A7 B7 五、發明説明（26Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The so-called “Aruchi-type group” in this article refers to the group with the following structure: This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 V. Description of Invention (26

R14 R16· 或R14 R16 or

或 R13Or R13

ϋ 上示基團1至1L中所用之Ζ，Ζ 1，Ζ 2，R 1 1，R 1 2， R 13，R 14，R 15，R 16，R 15a及R 16a乃如同上文所述 〇 理想之式I及Π化合物爲其中 R 1爲 或 經濟部中央標準局員工消費合作社印製 R12 R11Ζ Z, Z 1, Z 2, R 1 1, R 1 2, R 13, R 14, R 15, R 16, R 15a and R 16a used in the groups 1 to 1L are as described above. 〇The ideal compounds of formula I and Π are R12 or R11 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs.

R15 者（包括其中Z1爲一個鍵且R11爲烷撐 —NH—C- II 0 或烯撐且Z 2爲 (請先閲讀背面之注意事項再填寫本頁)R15 (including where Z1 is a bond and R11 is alkylene —NH—C-II 0 or olefinic and Z 2 is (Please read the precautions on the back before filling this page)

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 29 _ 486469 A7 B7 五、發明説明（27 ) —c3 k基或1 ，1 ，1 一三氟乙基，R13爲Η或F且 (請先閲讀背面之注意事項再填寫本頁) R15爲Η或F，且Ζ爲一個鍵或〇者；及其中R1:爲烷撐 或烯撐或被合氧基取代之烷撐，Ri2爲烷基，烯基，芳烷 基，芳烯基，Ζ爲〇，S或一個鍵者） 結構I中，R2，R3，及最好各爲η且X最好爲 C Η 2 ，CH2CH2 或 CH=CH。 結構Π中，R6最好爲Η或CH3且R5最好爲環烷 基’苯基’芳基或雜芳基，或鄰位具有疏水取代基亦即烷 基，烷氧基，鹵烷基（最多含五個鹵基團），三氟甲基， 芳基，芳氧基，芳烷基，芳烷氧基，鹵烷氧基（最多含五 個鹵基團）之環烷基，苯基，芳基或雜芳基。 導致化學不安定性分子之結合取代基當然不包括在本 發明範圍內；例如，本發明化合物不包括一 0 - 0， 一〇一C — OH，N — C-OH 及一 S — C 一 0H 鍵結。 式I ，I i ，Π及Π i化合物可藉由下列反應圖中所 述之例證方法製得，·這些反應之例證試劑及步驟乃示於下 文及實例中。 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐3〇 一 486469 A7 B7 五、發明説明（28 ) 反應圖I•製備異吲跺滿酮哌啶I之路徑 〇 NR1 R，0^° r4 y 〇 R1* is R1 or (CH3)aCOCO {BOC]This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 29 _ 486469 A7 B7 V. Description of the invention (27) —c3 k-based or 1,1,1 trifluoroethyl, R13 is Η or F and (please read the notes on the back before filling this page) R15 is Η or F, and Z is a bond or 〇; and R1: is alkylene or alkylene or alkylene substituted with a oxy group, Ri2 is alkyl, alkenyl, aralkyl, arylalkenyl, Z is 0, S or a bond) In structure I, R2, R3, and preferably each η and X is preferably C Η 2, CH2CH2 Or CH = CH. In the structure Π, R6 is preferably Η or CH3 and R5 is preferably a cycloalkyl 'phenyl' aryl or heteroaryl group, or a hydrophobic substituent in the ortho position, that is, an alkyl group, an alkoxy group, or a haloalkyl group ( Contains up to five halo groups), trifluoromethyl, aryl, aryloxy, aralkyl, aralkoxy, haloalkoxy (up to five halo groups) cycloalkyl, phenyl , Aryl or heteroaryl. Binding substituents that cause chemically unstable molecules are of course not included in the scope of the present invention; for example, compounds of the present invention do not include a 0-0, 10-C-OH, N-C-OH, and an S-C-0H bond Knot. Compounds of formula I, I i, Π and Π i can be prepared by the exemplified methods described in the following reaction schemes. Illustrative reagents and steps for these reactions are shown below and in the examples. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm 30-486469 A7 B7. V. Description of the invention (28) Reaction diagram I • Preparation of isoindolinone The path of pyrimidine 〇NR1 R, 0 ^ ° r4 y 〇R1 * is R1 or (CH3) aCOCO {BOC]

ISIS

NR1·NR1 ·

(請先閲讀背面之注意事項再填寫本頁) 裝· 經濟部中央標隼局員工消費合作社印製 反應圖II •製備異吲跺滿酮哌啶I之另一路徑(Please read the precautions on the back before filling out this page.) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, Reaction Diagram II • Another way to prepare isoindolinone piperidine I

鹵基 XI 訂 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 31 一 486469 A7 B7 五、發明説明（29 SSEU1 •藉烷基化或芳基化以將r 1置入之作用 R4 ifi：The paper size of the halogen-based XI edition applies to the Chinese National Standard (CNS) A4 (210X297 mm)-31-486469 A7 B7 V. Description of the invention (29 SSEU1 • By alkylation or arylation to place r 1 in Function R4 ifi:

R4 1Δ 圖IV- ·製備初始物質IV b及IV C之路揮 〇ί ο Η,Ν— iVa ΟR4 1Δ Figure IV- · Preparation of initial substances IV b and IV C. 〇ί ο Η, Ν— iVa Ο

IISIIISI

^N-CH2Ph ° yia 氫解作用 〇^~〇,^ N-CH2Ph ° yia hydrogenolysis 〇 ^ ~ 〇,

胺 烷基化或芳基化作用 P (如同反應圖III) 經濟部中央標準局員工消費合作社印製 〇 Ylc 肼解作用 Η*Ν—< N-R^ IVb hiw~^""^W-BOC IVc 胼解作用 〇 Yib 式Λ。义。七 kBOC 酐'Amine alkylation or arylation P (as shown in reaction diagram III) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Ylc Hydrazine Η * N— < NR ^ IVb hiw ~ ^ " ^ W- BOC IVc decomposes. Yib formula Λ. Righteousness. Seven kBOC anhydride '

CcJn-Cn-boc 〇 m (請先閱讀背面之注意事項再填寫本頁)CcJn-Cn-boc 〇 m (Please read the notes on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -32 - 486469 A7 B7 五、發明説明（3〇 厘應阚V- •製備初始物質IV b之一般路徑 ( ^HtPh IVa 繼曹 PG»N —'{ N-CH2Ph m 氩解作用 胺 \ 烷基化或芳基化作用 PG-N-< ^~"-- PG-N-/-XF ^ (如同反應圖ΙΠ > ^， 施 Xllb 去保護作用 Μ 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁)This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -32-486469 A7 B7 V. Description of the invention (30% should be V- • General route for preparing the initial substance IV b (^ HtPh IVa Following Cao PG »N — '{N-CH2Ph m argon-decomposed amine \ alkylation or arylation PG-N- < ^ ~ "-PG-N-/-XF ^ (as shown in Reaction Diagram Π > ^, Protected by Xllb M Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page)

本紙張尺度適用中國國家標準（CNS)A4現格（ 210X297公釐）_ 33 486469 A7 B7 五、發明説明（31 ) 反應SiVIRVli •製備II之一般路徑 醯胺形成作用This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) _ 33 486469 A7 B7 V. Description of the invention (31) Reaction SiVIRVli • General route for the preparation of II Amine formation

H-R1 又 烷基-Ο N- 〇H-R1 and alkyl-〇 N- 〇

〇 RS^N—^ (請先閲讀背面之注意事項再填寫本頁) 〇〇 RS ^ N— ^ (Please read the notes on the back before filling this page) 〇

N-R1 XXTTa 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_料_ 486469 A7 B7 五、發明説明（32 ) 反應圖VIM化合物I A1，I A2之製備N-R1 XXTTa Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs This paper is printed in accordance with the Chinese National Standard (CNS) A4 (210X297 mm) Preparation of A1, I A2

.鹼 R10CON(OMe)Me 或 DMF(R10isH) 醯化作用 (請先閲讀背面之注意事項再填寫本頁) R1 0 R3 R4.Base R10CON (OMe) Me or DMF (R10isH) Tritiation (Please read the notes on the back before filling this page) R1 0 R3 R4

R10 R· 脫水作用 氫化作用R10 R · Dehydration Hydrogenation

R1 R4 ΙΑ2 ΟR1 R4 ΙΑ2 Ο

R10 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）^ 35 _ 486469 A7 B7 五、發明説明（33 ) 反應圖IX化合物I Α3 — I Α6之製備R10 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs This paper is printed in accordance with Chinese National Standard (CNS) A4 (210X297 mm) ^ 35 _ 486469 A7 B7 V. Description of the invention (33) Reaction chart IX Compound I Α3 — I Preparation of Α6

Ri.O^KDNH R4 xxm 或 le，Ri.O ^ KDNH R4 xxm or le,

ΙΑ3 觭ΙΑ3 觭

XXIVXXIV

(M=金屬諸如 L i，或Mg或Zn) ΙΑ4(M = metal such as Li, or Mg or Zn) ΙΑ4

加成作用 r34mXXIV ΙΑ4 (請先閲讀背面之注意事項再填寫本頁) 【裝· 訂 烷基化作用 R35鹵基 去氧作用 或 氫解作用Addition r34mXXIV ΙΑ4 (Please read the precautions on the back before filling in this page) [Packing · Order Alkylation R35 Halo Deoxygenation or Hydrogenolysis

ΙΑ5 經濟部中央標準局員工消費合作社印製ΙΑ5 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ _ 486469 A7 _B7_ 五、發明説明（34 ) R 31及〜R 3 2各自由R 2，R 3或R 4基團中之任一者中所擇 定； R33及R3 4乃各自由R1基團中之任一者，以及芳氧 基，烷氧基，芳烷氧基，雜芳基烷氧基及雜芳氧基中所擇 定，R33及R34中至少有一者爲R1基團； R 35可爲R1基團中之任一者。 反應圖X及X I 化合物I A 7之製備 R4This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 486469 A7 _B7_ V. Description of the invention (34) R 31 and ~ R 3 2 are each selected from the group of R 2, R 3 or R 4 R33 and R3 4 are each selected from any one of R1 groups, and among aryloxy, alkoxy, aralkoxy, heteroarylalkoxy and heteroaryloxy Alternatively, at least one of R33 and R34 is an R1 group; R 35 may be any one of R1 groups. Reaction Diagrams X and X I Preparation of Compound I A 7 R4

還原作用 Z η，A c 0 H或 E t3S i Η，三氟乙酸 (請先閲讀背面之注意事項再填寫本頁)Reduction Z η, A c 0 H or E t3S i Η, trifluoroacetic acid (Please read the precautions on the back before filling this page)

HaN—< N- R1 IVb 烷基化作用 h N-R1 ---- R3-[I 1) 鹸 2) Re鹵基 (鹵基=l,Br,C〇HaN— < N-R1 IVb alkylation h N-R1 ---- R3- (I 1) 鹸 2) Re halo (halo = 1, Br, C.

經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ 3了 一 486469 A7 B7 五、發明説明（35 ) ~ 反應圖X Π 化合物Π之製備 (Robotic醯胺偶合作用）Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics The paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) _ 3 486469 A7 B7 V. Description of the invention (35) ~ Reaction Diagram X Π Preparation of Compound Π (Robotic amine coupling)

XXVIIXXVII

XXVIXXVI

0 .II R5—C-OH0 .II R5—C-OH

XXVIII 游離鹼化 HW—^ N- R1 ReXXVIII Free alkalization HW— ^ N- R1 Re

XXVIIXXVII

R5-C—N—( N—R1 (請先閲讀背面之注意事項再填寫本頁)R5-C—N— (N—R1 (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 下列反應圖XE等反應圖中，在芴基環或芴基類似物 中，稠合芳基團： 可各任被本文所定義之5 -或6 —節雜 芳基環所替代。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 38 _ 486469 A7 B7 五、發明説明（36 ) 1 i 反應圖XIII—其中Z2爲S，S 0或S 〇2之中間體之製備The following reaction diagrams, such as XE and other reaction diagrams, are printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. In the fluorenyl ring or fluorenyl analogue, the fused aromatic groups can be defined as 5-or 6- Heteroaryl ring is replaced. This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) _ 38 _ 486469 A7 B7 V. Description of the invention (36) 1 i Reaction Diagram XIII-where Z2 is an intermediate of S, S 0 or S 〇2 Preparation

(請先閲讀背面之注意事項再填寫本頁) ;裝_ 烷基化作用 1}强鹸 2}XLr”一Yi(Please read the precautions on the back before filling this page); Packing_ Alkylation 1} Strong 鹸 2} XLr ”一 Yi

I化作用 1) 强鹼 2) X^R^-Y1 烷基化作用Iization 1) Strong base 2) X ^ R ^ -Y1 alkylation

訂 經濟部中央標準局員工消費合作社印製 X1，y1乃相同或互異之鹵基或〇磺酸鹽 η = 1 或2 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_的_ 486469 A7 B7 五、發明説明（37 ) 屎應_ XIV - Α (其中z2爲NHCO之中間體）之製備Order X1 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, y1 is the same or different halo or sulfonate η = 1 or 2 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ _ 486469 A7 B7 V. Description of the invention (37) Preparation of feces should _ XIV-Α (where z2 is an intermediate of NHCO)

醯胺形成作用Formamide

烷基化作用 1) 之2當量之鐮 1)之2當量之鹸2) 之1當量之X1-R”一Yi 2)之1當量之X1, rM-Y1Alkylation 1) 2 equivalents of sickle 1) 2 equivalents of 鹸 2) 1 equivalent of X1-R "-Yi 2) 1 equivalent of X1, rM-Y1

醯胺形成作用 烷基化作用Alkylamine formation alkylation

(請先閲讀背面之注意事項再填寫本頁) ;裝. 、?! 經濟部中央標隼局員工消費合作社印裝 X1，Y1爲相同或互異之鹵基或0磺酸鹽 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 4Q _ 486469 A7 B7 五、發明説明（38 )(Please read the precautions on the back before filling this page); Install.,?! The X1 and Y1 are the same or different halogen or 0 sulfonate printed on the employee consumer cooperative of the Central Bureau of Standards, Ministry of Economic Affairs. China National Standard (CNS) A4 specification (210X297 mm) _ 4Q _ 486469 A7 B7 V. Description of invention (38)

反應圖X IV A 供製備中間體X L之另一步驟 (示於反應圖XIV中）Reaction Diagram X IV A for another step of preparing intermediate X L (shown in Reaction Diagram XIV)

進行上示反應時，鹼諸如正丁基鋰，雙（三甲基甲矽烷基 )胺化鋰及雙（三甲基甲矽烷基）胺化鈉可於質子情性溶 劑諸如四氫呋喃中，於一 L 8 °C至3 5 °C間使用。 最好令初始物質及異氰酸酯（R12N = C-0)共同於溶 劑中反應，而後將鹼加入，繼而任將過量之異氰酸酯加入 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）乂 41 - 486469 A7 B7 Η 五、發明説明（39 ) 辰應圖XV—其中Ζ 1爲一 Ν — C 一之中間體之製備When carrying out the reaction shown above, bases such as n-butyllithium, lithium bis (trimethylsilyl) amide and sodium bis (trimethylsilyl) amide can be used in a protic solvent such as tetrahydrofuran. L Use between 8 ° C and 3 5 ° C. It is best to let the initial substance and isocyanate (R12N = C-0) react together in the solvent, and then add the base, and then add the excess isocyanate (please read the precautions on the back before filling this page). Central Bureau of Standards, Ministry of Economic Affairs The paper size printed by the employee consumer cooperative is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 乂 41-486469 A7 B7 Η 5. Description of the invention (39) Chen Ying Figure XV-where Z 1 is a Ν-C a Preparation of intermediates

II 0II 0

醯胺形成作用 ΗΟ—R11-Formamide formation ΗΟ—R11-

鹵化作用或 XLllfl 磺化作用Halogenation or XLllfl sulfonation

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（€奶）八4規格（210父297公釐）_42_ 486469 A7 B7(Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This paper size applies to the Chinese national standard (€ milk) 8 4 specifications (210 parent 297 mm) _42_ 486469 A7 B7

五、發明説明（4〇 ) 反應圖XVIV. Description of the invention (40) Reaction diagram XVI

格利雅 加成作用 R12MgXGrignard R12MgX

酸處理Acid treatment

XLV Y2 — R11 — SH V2 - OPG ^ COOM· 9^2爲保護基晒师XLV Y2 — R11 — SH V2-OPG ^ COOM · 9 ^ 2

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

酸處理 、τAcid treatment, τ

HO—< Z Y2_ Rn_ SH Y2-OPG 或 COOMeHO— < Z Y2_ Rn_ SH Y2-OPG or COOMe

XLVIIXLVII

Rn R14 XXXV 經濟部中央標準局員工消費合作社印製Rn R14 XXXV Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

烷基化作用 1) 强鹼 2) X^R12 X歯基或0磺酸鹽Alkylation 1) Strong base 2) X ^ R12 Xfluorenyl or 0 sulfonate

XLVI 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ “ _ 486469 A7 B7 五、發明説明（41 )XLVI This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) _ "_ 486469 A7 B7 V. Description of the invention (41)

還原作用 (Υ2·0Ο2Μθ) (Y2-OPG)Reduction (Υ2.02Mθ) (Y2-OPG)

XLVI XLVill 鹵化作用XLVI XLVill Halogenation

XL VIII 或磺化作用XL VIII or sulfonation

XXXIIIE (請先閲讀會面之注意事項再填寫本頁) •祕衣_ 硫 氧化作用XXXIIIE (Please read the notice before meeting and then fill out this page) • Secret Clothes _ Sulfur Oxidation

XXXIIIEXXXIIIE

XXXIIIF(n:1} XXXIIIG (ns2) 訂 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS) A4規格（ 210X297公釐）_ 44 _ 486469 Α7 Β7 五、發明説明（42 ) 反應圖XVIA酮之製備XXXIIIF (n: 1) XXXIIIG (ns2) Printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperatives. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ) Preparation of XVIA ketone

2)供 G » Μ外一用之醯胺形成作用 ΟΜθ2) Formamide for G »Μ external use 〇Μθ

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

*1T 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ “ 486469 A7 B7 五、發明説明（43 ) 反應圖XV IΒ •酮之製備（理想路徑） 烷基化作用* 1T Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ "486469 A7 B7 V. Description of the invention (43) Reaction diagram XV IB • Preparation of ketones ( Ideal path) alkylation

HOOCHOOC

鹵基或 略〇 — Rn 0 一磺酸鹽 feR1s 2)PG.0R^X1 «〇〇0\尸^ 去羧基化作用Halo or slightly 0 — Rn 0 monosulfonate feR1s 2) PG.0R ^ X1 «〇〇0 \ Corps ^ decarboxylation

DMSO, RT R13 \jr^uDMSO, RT R13 \ jr ^ u

XXXIXXXXIX

XLIICXLIIC

1}i去保護作用 Μ用 (請先閲讀背面之注意事項再填寫本頁)1) i to protect the role of Μ (please read the precautions on the back before filling this page)

Ρ£盪適苔之保護基團：翳纖 11%用 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）^ 46 486469 A7 B7 五、發明説明（44 ) . 反應圖XV IA—醯胺鍵結性化合物之製備R1· 1)鐮 2>汐.1111.(：02烷基 R1 ho2c、 ho2c- z R14P £ The protective group suitable for moss: 11% of fiber is printed with the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Explanation (44). Reaction diagram XV IA—Preparation of amine-bonded compounds R1 · 1) Sickle 2> Xi. 1111. (: 02 alkyl R1 ho2c, ho2c-z R14

其中X1爲鹵基或 o2c-r^ ο-磺酸鹽XLVWhere X1 is halo or o2c-r ^ ο-sulfonate XLV

RuRu

XXXIXXXXIX

ris^0^r14 皀化作用 R12、 醯胺 形成作用ris ^ 0 ^ r14 Tritiation R12, Triamine formation

XLVIIXLVII

r13>^r14 r12nh 2r13 > ^ r14 r12nh 2

(請先閲讀背面之注意事項再填寫本頁) •ηιι衣· 醯胺形成作用(Please read the precautions on the back before filling in this page)

XLVIIAXLVIIA

XLVIII R· is 訂 線 經濟部中央標準局員工消費合作社印製 ne r· or R4 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）—47 _ 486469 A7 B7 五、發明説明（45 ) 反應圖XV I I B—胺基甲酸鹽及掘嫌結件彳h合物之製備XLVIII R is is printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Ne r · or R4 This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)-47 _ 486469 A7 B7 V. Description of the invention (45 ) Reaction Diagram XV IIB-Preparation of Carbamates and Compounds

(請先閲讀背面之注意事項再填寫本頁) • 衣. 爲脫離基圆 »3 讀j?C6H4一 p — NO2 或N1-咪唑，且L爲0或NHCH2 :h2(Please read the notes on the back before filling this page) • Clothing. To get rid of the base circle »3 Read j? C6H4a p — NO2 or N1-imidazole, and L is 0 or NHCH2: h2

、1T r = ch=ch2 1>臭氧 2) NaBH41T r = ch = ch2 1 > Ozone 2) NaBH4

w、w· 經濟部中央標準局員工消費合作社印製w, w · Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

其中L爲0或HNWhere L is 0 or HN

R1 線 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469 A7 B7 五、發明説明（46 ) 厘廬匿2L3LLULA—磺醯胺之形成 Η R*R1 line This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297mm) 486469 A7 B7 V. Description of the invention (46) Lilu 2L3LLULA-the formation of sulfonamide Η R *

tvb xmtvb xm

r5so2ci LXr5so2ci LX

O r5-s I蠢 OR LXIO r5-s I stupid OR LXI

M- R1 上於爸種不同溶劑（二氯甲烷，四氫映晡，胂醅^ 中，任於三級胺鹸諸如吡啶或三乙晨在举|▲應) 反應圖XV I I IB—脲之形成《R5爲胺基） K> ivb. xmIn M-R1, different solvents (dichloromethane, tetrahydrofluorene, 胂 醅 ^, and tertiary amines such as pyridine or triethene are in use | ▲ 应) Reaction Diagram XV II IB—Urea Forms "R5 is an amine group" K > ivb. Xm

Rr.NsC=0 ~v-^ Ά：〇βι LX" 4頃ί M?! i =。•於貯麵諸如甲苯 (爲烷基，芳基，雜芳基或芳烷基） 反應ax IXa—製備終產物之一般路徑Rr.NsC = 0 ~ v- ^ Ά: 〇βι LX " 4 are ί M ?! i =. • Reaction on a storage surface such as toluene (for alkyl, aryl, heteroaryl or aralkyl) ax IXa—general route to the final product

W-H (請先閲讀背面之注意事項再填寫本頁) < 11 (其中R1乃如同於 墨親或 其它R1)W-H (Please read the notes on the back before filling out this page) < 11 (where R1 is the same as Mo Qin or other R1)

XLVIIA 胺烷基化作用XLVIIA Amine Alkylation

或 II 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS>A4規格（ 210X297公釐）_ 49 486469 A7 B7 五、發明説明（4?) 反應圖XIXB製備終產物（I或I I )之一般路徑R1. X1 XUC 繼pi反述 胺烷基化作用 PG-N—( N- R1 m 去保護作用 終產物 (I 或 II)Or II Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy The paper size is applicable to Chinese national standards (CNS > A4 size (210X297 mm) _ 49 486469 A7 B7 V. Description of the invention (4?) Or II) the general path R1. X1 XUC follows pi to paraphrase amine alkylation PG-N— (N- R1 m deprotection end product (I or II)

如同反應圖 I. lit VI, νΐίι, xf XI,XVIIIA, XVIIBAs the reaction diagram I. lit VI, νΐίι, xf XI, XVIIIA, XVIIB

(绎焊譆氮(PG — N)之實例爲t _B u OC = ONH ( BOC， ▲萃聽下，諸如使用無水氫氯§之兰4晨 (請先閲讀背面之注意事項再填寫本頁) 襄· 訂 線 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -50 - 486469 A7 B7 五、發明説明（48 ) ^®2L2L-於反應序列終端時之硫之氧化作用 铲一< M-R11(An example of welding Nitrogen (PG — N) is t _B u OC = ONH (BOC, ▲ Excerpt, such as the use of anhydrous hydrogen chloride § blue 4 morning (Please read the precautions on the back before filling this page) Printed by the Central Bureau of Standards of the Ministry of Economic Affairs, Employees' Cooperatives. The paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) -50-486469 A7 B7 V. Description of the invention (48) ^ ® 2L2L Oxidation of Sulfur at the End of Sequence-M-R11

”Hcr 或 cf3co2h· 2) 選擇性 硫化作用3) 鹼”Hcr or cf3co2h · 2) Selective sulfuration 3) Alkali

(Re乃如同於反應圖XV I IA中所述） (請先閲讀背面之注意事項再填寫本頁) 1^· 訂 經濟部中央標準局員工消費合作社印製 ----—^—^—^—^1^—^—· 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 51 __ 486469 A7 B7 五、發明説明（49 ) MMMXJLL-鹵化物中間膛之製備 ，Rie ho2c- z R14(Re is as described in the reaction chart XV I IA) (Please read the notes on the back before filling out this page) 1 ^ · Order printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ----— ^ — ^ — ^ — ^ 1 ^ — ^ — · This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm)-51 __ 486469 A7 B7 V. Description of the invention (49) MMMXJLL- Preparation of halide intermediate chamber, Rie ho2c -z R14

XXXIX 經濟部中央標準局員工消費合作社印製 Η H (烷基或芳基） 耙催化劑 驗 質子惰性溶劑XXXIX Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Η H (alkyl or aryl) Rake catalyst Test Proton inert solvent

LXVILXVI

•c=c I I ho2c• c = c I I ho2c

把催化劑 m 質子惰性溶劑 麵：鈀催化劑可爲P d ( P h 3p ) 4， ΐ¥ΐίί、1旦或雙（三甲基甲砂燒基）乙醯胺， Pr惰眷鑾豐2畫1霞壁喃甲基甲酿哼或混合物， 1£二3愚葚缉1矽烷基，諸如t 一Bu (Ph)2s i -且去保_狀況可虑η - B u 4N F，四氫咲喃。 去保護作用Proton inert solvent of catalyst m: palladium catalyst can be P d (P h 3p) 4, 旦 ¥ ΐίί, 1 denier or bis (trimethylmethanyl) acetamide, Pr inferiority 2 Salmonan methyl methyl succinate or mixture, 1 二 2 3 葚 1 silane, such as t 1 Bu (Ph) 2s i-and deprotection conditions can be considered η-B u 4N F, tetrahydropyran . Deprotection

LXVII (請先閲讀背面之注意事項再填寫本頁) 衣. 訂 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ _ 486469 A7 B7 五、發明説明（5〇 )LXVII (Please read the precautions on the back before filling out this page) Clothing. The size of this paper applies the Chinese National Standard (CNS) A4 (210X297 mm)

鹵化物形成作用Halide formation

鹵索爲Cl, Br, I 黯霉用Halogen for Cl, Br, I

R 15 (請先閲讀背面之注意事項再填寫本頁) ·裝，R 15 (Please read the notes on the back before filling this page)

、1T 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 53 ^ 486469 A7 B7 五、發明説明（51 ) 反ISWXX I M.一卜®®舰__筲之製備 R'-X1 爲本文所述之任何 X1=鹵基或〇礙酸鹽 〇 胺烷基化作用1, 1T Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-53 486 469 A7 B7 V. Description of the invention (51) Anti-ISWXX I M. Yibu ® ® 舰 __ 筲 的 制造 R'-X1 is any of the X1 = halo or alkanoate amine alkylation described herein

pOjEt R1 — NpOjEt R1 — N

CQ2Et K〇H?®?HC 1CQ2Et K〇H? ®? HC 1

HN^〇CH2ph Ph2P〇N3, Et3N :而後 PhCH2OHHN ^ 〇CH2ph Ph2P〇N3, Et3N: then PhCH2OH

COOH 去保護作用 H2, Pd(OH)2/C NH3COOH deprotection H2, Pd (OH) 2 / C NH3

R1 - N、 •HCI (請先閲讀背面之注意事項再填寫本頁) €今 訂 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -54 - 486469 A7 _B7___五、發明説明（52 ) 中，間體Ω可用以作爲初始物質以經由與本文之反應圖 ，尤其是與反應圖I ，π，ιν，ν，νι，νπ，Μ，χ， ΧΙ ，ΧΠ ，ΧΜΑ，ΧΜΒ ，ΧΚΒ ，ΧΧ，ΧΧ1Ε 中 所述相同之方法以製得3 —經取代異構體I丨及Π i 。 反應圖X X III —式I及Π化合物之N —氧化物之製備 M-R1 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 反應圖 ，X Μ B， 發明式I或 異構體之初 取代而得相 取代哌啶異 上示反 醇 X X X V ，及醯胺X 或如同1， ，醇，酮， 反應圖I至 I 至 VI， X K A， Π化合物 始物質當 關之本發 構體。 應圖X Π ，酸X X L基團可 L· i及 氫化物及 X X m之 Μ 至 ΧΠ，XVHA，XVHB，XMA XKB，XX及XXI (其相當於本 之製備）中，述及爲4 -經取代哌啶 然可被相關之3 -經取代哌啶異構體 明I i或E i化合物，其包括3 -經 至XX I中，初始芴基型酸XXVBI， XK及XL Π，酮XLIV，氫化物X 彼如同11所示之含芴基基團 /或]^所示之含茹基型基團之相關酸 醯胺所取代以得中間化合物以供製備 本發明式Ι，Ι>，Π或化合物 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） -55 - 486469 經濟部中夬標準局員工消費合作社印製 A7 _____B7_. _五、發明説明（53 ) 酞懂亞胺形成作用（反應圖I ，IV)可藉於油浴中， 任於惰性溶劑中加熱至約8 0至1 5 0°C或藉技藝中已知 之各種不同之其它步驟來進行。 還原作用（反應圖I )可藉以還原劑諸如鋅，於乙酸 或錫之存在下，於氫氯酸之存在下，於惰性氣層下（例如 氬）處理來進行。 異蚓跺酮形成作用（反應圖I )可藉於約5 0至 1 5 0°C之範圍內，於有機溶劑（例如甲苯，乙醇，二甲 基甲醯胺）中，任於鹽（例如碳酸鉀）或三級胺鹼（例如 2，6 —二特丁基吡啶或三乙胺）之存在下加熱來進行。 醯胺形成作用（反應圖11，贝，狐，逦，又，又1， ΧΠ ，XIV，XIVA，XV，XVI，XVI，XVIA， XVEA，XVEB，XX I )可藉技藝中已知之許多方法來 進行。例如，胺基質可（1 )以醯基鹵R5C (0)鹵基 或化合物X或XA，於質子惰性溶劑中，任於三級胺鹼（ 例如三乙胺）之存在下處理；（2 )以醯基鹵於水性鹼之 存在下，於史考頓-鮑曼狀況下處理；（3 )以游離羧酸 (R5C 02H )於偶合劑諸如二環己基碳化二亞胺（ DCC)，二異丙基碳化二亞胺（DIC)或1 一（3-二甲胺基一丙基）一 3 -乙基碳化二亞胺氫氯酸鹽（ WSC)之存在下，任於1 一羥基苯並三唑（Η0ΒΤ) 之存在下處理；（4)以游離酸於N，N -羰基二咪唑之 存在下，於質子惰性有機溶劑中處理，繼而以胺基質處理 ;(5 )以三烷鋁（例如A ( C Η 3 ) 3 )於質子惰性溶 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） -56 - 486469 經濟部中央標準局員工消費合作社印製R1-N, • HCI (please read the notes on the back before filling this page) € This order is printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperatives. This paper applies the Chinese National Standard (CNS) A4 (210X297 mm)- 54-486469 A7 _B7___ V. In the description of the invention (52), the interstitial Ω can be used as the initial substance to pass the reaction diagram with this article, especially with the reaction diagram I, π, ιν, ν, νι, νπ, M, χ, χΙ, χΠ, χΜΑ, χΜΒ, χΚΒ, Χχ, ΧχΕ and the same method described above to obtain the 3-substituted isomers I 丨 and Πi. Reaction Diagram XX III-Preparation of N-Oxide of Compounds of Formula I and Π M-R1 (Please read the notes on the back before filling this page) The reaction chart printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, X Μ B, The initial substitution of formula I or isomers to obtain the phase-substituted piperidine is shown in the reverse alcohol XXXV, and amidine X or as 1, 1, alcohols, ketones, reaction diagrams I to I to VI, XKA, Π compounds starting materials The essential structure of the moment. According to the figure X Π, the acid XXL group may be L · i and hydride and XX to ΜΠ to XΠ, XVHA, XVHB, XMA XKB, XX and XXI (which are equivalent to the preparation of this), and is described as 4- Substituted piperidine can be related to 3-substituted piperidine isomers Ming I or E i, which include 3- to XX I, the initial fluorenyl acids XXVBI, XK and XL Π, ketone XLIV, The hydride X is substituted with a fluorenyl group-containing group as shown in 11 and / or a related acid sulfonylamine group with a sulfonyl group as shown in 11 to obtain an intermediate compound for the preparation of the formula I, I >, Π of the present invention. Or the size of this paper applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -55-486469 Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs A7 _____B7_. _V. Description of the invention (53) The action (reaction diagrams I, IV) can be performed by heating in an oil bath to about 80 to 150 ° C in an inert solvent or by various other steps known in the art. The reduction (Scheme I) can be performed by a reducing agent such as zinc in the presence of acetic acid or tin, in the presence of hydrochloric acid, and under an inert gas layer (such as argon). Isoprocanone formation (Scheme I) can be used in organic solvents (such as toluene, ethanol, dimethylformamide) in the range of about 50 to 150 ° C, such as salts (such as Potassium carbonate) or a tertiary amine base (e.g., 2,6-di-tert-butylpyridine or triethylamine). The formation of amidine (Reaction Figure 11, Shellfish, fox, salamander, yet another, χΠ, XIV, XIVA, XV, XVI, XVI, XVIA, XVEA, XVEB, XX I) can be obtained by many methods known in the art get on. For example, the amine matrix can be (1) treated with a fluorenyl halide R5C (0) halo or compound X or XA in an aprotic solvent in the presence of a tertiary amine base (such as triethylamine); (2) Treated with stilbene halide in the presence of aqueous base under Scootton-Baumann condition; (3) Free carboxylic acid (R5C 02H) in a coupling agent such as dicyclohexylcarbodiimide (DCC), diiso Propylcarbodiimide (DIC) or 1- (3-dimethylaminomonopropyl) -3-ethylcarbodiimide hydrochloride (WSC) in the presence of 1-hydroxybenzo (4) treatment with a free acid in the presence of N, N-carbonyldiimidazole in an aprotic organic solvent, followed by treatment with an amine matrix; (5) treatment with aluminum trialkane ( For example, A (C Η 3) 3) is inert to protons (please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -56-486469 Central Ministry of Economic Affairs Printed by Standards Bureau's Consumer Cooperative

A7 __ B7_五、發明説明（54 ) 劑中處裡，繼而以酯（例如R 5 C 0 2烷基或化合物ΥΠΙ )處 理或（6)藉令酸與醯基氯（例如氯甲酸異丁酯或雙-（ 2 —合氧基一 3 —噁唑烷基）一膦醯氯（Bop — C5) 於三級胺鹼（例如三乙胺）之存在下起反應以達成混合酐 形成作用，繼而以胺基質處理。 甲烷磺酸鹽形成作用（反應圖Π)可藉將胺-醇基質 以甲烷磺醯氯及三乙胺或吡啶或於質子惰性溶劑諸如二氯 甲烷中處理來進行。 鹼環化作用（反應圖Π，Μ )可藉以鹼（例如特丁醇 鉀或氫化鈉）於惰性溶劑（例如二甲基甲醯胺，四氫呋喃 ，二甲氧基甲燒或甲苯）中處理來進行。Mitsunobu環化 作用（反應圖Π )可藉技藝中一般已知之方法來進行。例 如參見，R· K· Olsen, J. Qrg. Chem.· ϋ, 35 27 ( 1 984 );Gen i η, Μ. J·，et a 1. · J. Org. Chem. · 5 8· 2 3 3 4-7 (1993) 0 此外，化合物iy及m之混合物可於單一罐中藉將此混 合物於質子溶劑（例如水，甲醇，乙醇或異丙醇或其混合 物）中，於10 0至2 0 0 °C下加熱而轉換成化合物I a ，例如參見歐洲專利申請書81/26，749， F R 2，548，6 6 6 (1983)。 保護作用及去保護作用（反應圖m，iv，v，xvi， XVIB，ΧΚΒ，XXI )可藉技藝中一般已知之方法進 行。例如參見 T*. Greene, Protecting Groups in Organ i c Svnthes i s. Second edition, 1991。反應圖 V (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -57 - 486469 經濟部中央標準局員工消費合作社印製 A7 _____B7_ 五、發明説明（55 ) 中之代表氮保護基團。如同反應圖IV所示，一種特別 有用之基團爲特丁氧羰基（BOC)，其可由相關之酐中 衍出。經B 0 C保護之胺通常可以酸（例如三氟乙酸或氫 氯酸）依熟知技藝者詳知之步驟予以去保護。 氫解作用（反應圖HI，IV，V)可以氫使用氣球儀器 或帕爾搖動器於催化劑（例如鈀/活性碳）之存在下進行 〇 胺烷基化及芳基化作用（反應圖ΠΙ，IV，V，K， XE，XKA，XKB)可藉技藝中已知之方法進行。適 當之步驟乃述於 Cort izo, L. , J. Med. Chem. 3JL, 2242-2 247中。例如，烷基化及芳基化作用可藉將胺基質以鹵化 物（例如R1 —鹵基）或氧基甲苯磺酸酯（例如R1 — 〇 一甲苯磺酸酯）於質子惰性溶劑（例如二甲基甲醯胺）中 ，任於三級胺（例如三乙胺）或無機鹼（例如碳酸鉀）之 存在下處理來進行。 還原性胺化作用係在當R 1，R 6或R 7爲R 9R 10 C Η 一且R9及R1Q各爲氫，烷基，烯基，芳基，雜芳基，芳 烷基，雜芳基，烷基，環烷基，或環烷基烷基，或者R9 及R1Q共同爲烷撐（亦即R9R1QCH -形成環烷基團） 時，用以作爲先前胺烷基化作用之另一方法。此還原性胺 化作用可藉將胺以（a)酮或醛（R9 - C (0) - R1Q )，（b)NaBH4，NaBH3CN 或 NaB (乙醯氧基）3H，（c)質子溶劑（例如甲醇） 或偶極性質子惰性溶劑（例如乙睛）’且任以（d )酸（ (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） -58 - 486469 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（56 ) 例如ZT酸，三氟乙酸，氫氯酸或異丙醇酞）處理來進行β 當R1爲芳基或雜芳基時，過渡金屬（例如鈀或銅鹽或複 合物）可用以促進芳基化反應。 異吲跺酮之烷基化作用（反應圖X )可藉將異蚓跺酮 以強鹼（亦即雙（三甲基甲矽烷基）胺化鈉）或二異丙基 胺化鋰），繼而以烷基鹵（例如R 8 —鹵基）或磺酸烷酯 (例如R 8 —甲苯磺酸酯）於惰性溶劑（例如四氫呋喃或 二甲氧基乙烷）中處理來進行。此外，如同反應圖X及 X I中所見，胺IV b可於胺形成狀況下以結構X Β之酮處 理以得羥基內醯胺XXV，彼可使用還原劑諸如鋅，於乙 酸或三乙基矽烷中，於三氟乙酸中進行還原反應而得 I A 7 。 酞醯亞胺之胼解作用可藉技藝中已知之標準方法來進 行 0 例如參見 T. W. Greene, Protecting Groups in Organic Svnthes i s. Second edition, 1991 0 醯胺之N -烷華化作用（反應圖VI )可藉以鹼（例如 NaH，KH，KN〔Si (CH3)3〕2，K2C03， P4-phosphazene鹼，或丁基鋰）於質子惰性有機溶劑中處 理，繼而以R6 —鹵基或Re - 0 -甲苯磺酸酯處理來進 行。P-phosphazene 驗之用途乃述於 T. Pietzonka, D. Seebach , Angew. Chem. I n t. Ed. En cr 1 . 31 · 1481, 1992 中。 脫水作用（反應圖VID )可使用強酸諸如氫氯酸，硫酸 或三氟乙酸等來進行。 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 59 486469 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（57 ) 氫化作用（反應圖νπ ) 鉑或鍺之存在下，於氫氣層 反應圖Κ所示之加成反 劑X X IV，諸如有機鋰或有 或芳基）處理來進行。 去氧作用或氫化反應（ 乙酸或三氟化硼醚酸酯等之 基矽烷或參（三甲基甲矽烷 反應圖XDI，XIV，X 化作用係於鹼諸如丁基鋰或 等之存在下進行。R12Q中 任何R 12棊團。 此外，上示反應圖中之 之一者或二者均爲一個鍵時 基化步驟來進行。此反應中 化合物 xxvm，xxxvi， XLVE)與鹼（氫化鈉，雙 雙（三甲基甲矽烷基）乙醯 Pd(Ph3)4)及烯丙基 或 〜於惰 CHjC〇2CH-CH:CH2 ) 反應。此反應乃用以將一 R X1*：反應圖 xm，xiv，： 可於慣用催化劑諸如鈀/碳或 下進行。 應可藉將IA3以有機金屬試 機鎂化合物（其中有機爲烷基 反應圖K )係於強酸諸如三氟 存在下，於氫化物源諸如三乙 基）矽烷之存在下進行。 VI，XVIA，XVIB中之烷基 雙（三甲基甲矽烷基）胺化鈉 之R12咸知可爲上文所定義之 烷基化作用（當Z1或Z2中 )可使用鈀催化性烯丙基性烷 ，乃令芴基型或芘基型先質（ XXXVII，XXXIX，XL， (三甲基甲矽烷基）胺化鈉或 胺），鈀催化劑（例如 性乙酸酯（CH3C02CHrCH=CH4 性溶劑（例如四氫呋喃）中起 12(反應圖ΧΠ)或—R11 — CVI，XVIA)或一 R11 — (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 486469 經濟部中央標準局員工消費合作社印製 A7 __B7_五、發明説明（58 ) 〇Pf(反應圖XVIB，反應圖ΧΧί)置入。此反應之 產物乃含有以 開始之-R12基團或 一 R11 — X1 基團（或一 R11— OPG 基團）。R11 或 R12中烯之飽和作用可藉標準之催化性氫化狀況而完成。 反應圖X m，X vi及X νπ中之硫之氧化作用係進行如 下。 結構 XXXVI，ΧΧΧΜ，XXXDIE 及 I9 之硫化 物可藉1莫耳當量技藝中已知之試劑諸如3 0%過氧化氫 *高碘酸鈉，及過酸（例如間位一氯基過苯甲酸）而選擇 性地氧化成亞硕。所得之亞碉可更進一步藉另一莫耳當量 或過量之30%過氧化氫，過錳酸鉀，KHS05 ，或過 酸（例如間位-氯基過苯甲酸）而轉換成相關之硕。此外 ，硕亦可直接由硫化物與2莫耳當量或更多氧化劑諸如 3 0 %過氧化氫及過酸（例如間位-氯基過苯甲酸）中製 得。如果氧化期間有胺（諸如I 9中之哌啶）存在，則鹼 性氮可藉以酸諸如氫氯酸或三氟乙酸預處理而予以保護（ 參見反應圖X IX )。 欲製備其中Z1或Z2爲一 CHOH之實例，可將其 中Z1或Z2爲C=0之化合物，I ， I i ，Π及ni以 氫化物試劑例如氫硼化鈉還原。 本發明化合物可用以預防，安定化或導致哺乳類動脈 粥瘤硬化之消退，其係藉將有效醫療量之化合物予以投服 以降低Μ T P活性而達成。 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X 297公釐） -61 - 486469 A7 ___B7_ 五、發明説明（59 ) (請先閲讀背面之注意事項再填寫本頁) 本發明化合物可採用1 9 9 3年9月3日公布之美國 專利申請書系列第1 1 7，3 6 2號所示之步驟，並使用 由下列一種來源所離析出之Μ T P以測試Μ T P抑制活性 (1)牛肝之微粒體， (2 ) H e p G 2細胞（人類肝細胞瘤細胞）或 (3 )於杆狀病毒中所表現之再組合人類MT P。 本發明亦用以降低哺乳類血清脂肪濃度，諸如膽固醇 或三酸甘油酯（TG)濃度，其係藉將有效醫療量之化合 物予以投服以降低Μ T P之活性。 本發明化合物可用以治療其它各種需使用可降低 Μ Τ Ρ活性之製劑治療之病況或疾病。例如，本發明化合 物可降低MT Ρ之量或活性，因此可降低血清膽固醇及三 酸甘油酯值，故而有用以治療高膽固醇血症，高三酸甘油 酯血症，高脂肪血症，胰臟炎，高血糖症及肥胖症。 經濟部中夬標隼局員工消費合作社印製 本發明化合物舄可降低Μ Τ Ρ活性之製劑，故可投服 至需此治療之各種哺乳類，諸如猴，狗，貓，鼠，人類體 內。這些製劑可系統性地，諸如經口或非經腸部投服。 可降低MT Ρ活性或量之製劑可併成慣用之系統劑型 ，諸如片劑，膠囊，酏劑或可注射配方等，上示劑型亦包 括必要之生理上可接受性載體物質，賦形劑，潤滑劑，緩 衝劑，抗菌劑，膨脹劑（諸如甘露糖醇），抗氧化劑（抗 壞血酸或亞硫酸氫鈉）等。以口服劑型較理想，然而非經 腸部劑型亦相當令人滿意。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） -62 - 486469 A7 B7 五、發明説明（6〇 ) 投骤劑量必需根據病患年齡，體重及病況，以及投服 路徑，劑型及攝服法，及期望之結果而小心調整。通常， 上述劑型可以每日約5至約5 0 0毫克之量以單一或離散 劑量每日投服一至四次。 下列實例代表本發明之理想具體實施例。除非另有指 定，否則所有溫度均爲°C。 實例 9 一〔3 -〔4一（2，3 -二氫基一 1 一合氧基一 1H 一異巧丨晚一 2 -基）一1 一呢陡基〕丙基〕一 N -丙基一 9 H —窃一 9 —甲醯胺_____ (請先閱讀背面之注意事項再填寫本頁) A.A7 __ B7_V. Description of the invention (54) The agent is then treated with an ester (such as R 5 C 0 2 alkyl or compound ΥΠΙ) or (6) an acid and fluorenyl chloride (such as isobutyl chloroformate) Ester or bis- (2-hexyloxy-3-oxazolidinyl) monophosphine chloride (Bop-C5) reacts in the presence of a tertiary amine base (such as triethylamine) to achieve mixed anhydride formation. This is followed by treatment with an amine matrix. The methanesulfonate formation (reaction diagram Π) can be performed by treating the amine-alcohol matrix with methanesulfonyl chloride and triethylamine or pyridine or in an aprotic solvent such as dichloromethane. Alkali Cyclization (Reaction Diagram II, M) can be performed by treating a base (such as potassium t-butoxide or sodium hydride) in an inert solvent (such as dimethylformamide, tetrahydrofuran, dimethoxymethane or toluene). Mitsunobu cyclization (reaction diagram Π) can be performed by methods generally known in the art. See, for example, R · K · Olsen, J. Qrg. Chem. · Ϋ, 35 27 (1 984); Gen i η, M. J., et a 1. J. Org. Chem. 5 8 2 3 3 4-7 (1993) 0 In addition, a mixture of compounds iy and m can be used in This mixture is converted into compound I a by heating it in a proton solvent (such as water, methanol, ethanol, or isopropanol or a mixture thereof) at 100 to 200 ° C in a pot, for example, see European Patent Application Book 81 / 26,749, FR 2,548,6 6 6 (1983). Protective and deprotective effects (reaction diagrams m, iv, v, xvi, XVIB, KK, XXI) can be obtained by methods generally known in the art For example, see T *. Greene, Protecting Groups in Organ ic Svnthes i. Second edition, 1991. Reaction diagram V (Please read the notes on the back before filling out this page) This paper standard applies to Chinese National Standard (CNS) A4 Specifications (210X297 mm) -57-486469 Printed by A7 _____B7_, a consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. The representative nitrogen protecting group in the description of the invention (55). As shown in the reaction diagram IV, a particularly useful group It is tert-butoxycarbonyl (BOC), which can be derived from related anhydrides. B 0 C-protected amines can usually be deprotected with acids (such as trifluoroacetic acid or hydrochloric acid) according to procedures well known to those skilled in the art. Hydrogen Solution effect HI, IV, V) Hydrogenation can be performed using a balloon instrument or a Parr shaker in the presence of a catalyst (such as palladium / activated carbon). Amine alkylation and arylation (Reaction Diagrams II, IV, V, K, XE, XKA, XKB) can be performed by methods known in the art. Appropriate procedures are described in Cortizo, L., J. Med. Chem. 3JL, 2242-2 247. For example, alkylation and arylation can be achieved by using an amine matrix as a halide (such as R1-halo) or an oxytosylate (such as R1-〇-tosylate) in an aprotic solvent (such as two Methylformamide) is carried out in the presence of a tertiary amine (such as triethylamine) or an inorganic base (such as potassium carbonate). Reductive amination is when R 1, R 6 or R 7 is R 9R 10 C Η and R9 and R1Q are each hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaryl When alkyl, alkyl, cycloalkyl, or cycloalkylalkyl, or R9 and R1Q are both alkylene (ie, R9R1QCH-forming a cycloalkyl group), it is used as another method for the previous alkylation of amines. . This reductive amination can be achieved by using an amine with (a) a ketone or aldehyde (R9-C (0)-R1Q), (b) NaBH4, NaBH3CN or NaB (ethoxy) 3H, (c) a protic solvent ( (Such as methanol) or dipolar aprotic solvents (such as acetonitrile) 'and allowed (d) acid ((Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specifications ( 210X 297 mm) -58-486469 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (56) For example, ZT acid, trifluoroacetic acid, hydrochloric acid or isopropanolphthalein) treatment for β When When R1 is aryl or heteroaryl, transition metals (such as palladium or copper salts or complexes) can be used to promote the arylation reaction. The alkylation of isoindolinone (Scheme X) can be achieved by isoisofluorenone with a strong base (ie, sodium bis (trimethylsilyl) amide) or lithium diisopropylamide), This is followed by treatment with an alkyl halide (such as R 8 -halo) or an alkyl sulfonate (such as R 8 -tosylate) in an inert solvent (such as tetrahydrofuran or dimethoxyethane). In addition, as can be seen in Reaction Diagrams X and XI, amine IV b can be treated with a ketone of structure X B under amine formation conditions to obtain hydroxylactam XXV, which can be reduced with a reducing agent such as zinc in acetic acid or triethylsilane In acetic acid, a reduction reaction was performed in trifluoroacetic acid to obtain IA 7. The disintegration of phthalimide can be performed by standard methods known in the art. For example, see TW Greene, Protecting Groups in Organic Svnthes i s. Second edition, 1991 0 ) Can be treated with a base (such as NaH, KH, KN [Si (CH3) 3] 2, K2C03, P4-phosphazene base, or butyl lithium) in an aprotic organic solvent, followed by R6-halo or Re-0 -Tosylate treatment is performed. The use of the P-phosphazene test is described in T. Pietzonka, D. Seebach, Angew. Chem. I n. Ed. En cr 1. 31 · 1481, 1992. Dehydration (VID) can be performed using strong acids such as hydrochloric acid, sulfuric acid or trifluoroacetic acid. (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 (210X 297 mm) 59 486469 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 57) Hydrogenation (reaction diagram νπ) In the presence of platinum or germanium, the addition reaction agent XX IV shown in the hydrogen layer reaction diagram K, such as organolithium or aryl, is performed. Deoxygenation or hydrogenation reaction (acetic acid or boron trifluoride etherate, etc. of base silane or ginseng (trimethylsilane reaction diagram XDI, XIV, Xation is carried out in the presence of a base such as butyl lithium or the like . Any R 12 棊 group in R12Q. In addition, one or both of the reaction diagrams shown above are carried out by a bond time basification step. In this reaction compounds xxvm, xxxvi, XLVE) and a base (sodium hydride, Bis (trimethylsilyl) acetamidine Pd (Ph3) 4) and allyl or ~ inert CHjC2CH-CH: CH2) reaction. This reaction is used to convert an R X1 *: reaction diagram xm, xiv,: to a conventional catalyst such as palladium / carbon or. It should be possible to test IA3 with organometallic magnesium compounds (wherein the organic is an alkyl reaction scheme K) in the presence of a strong acid such as trifluoro, in the presence of a hydride source such as triethyl silane. R12 of alkyl bis (trimethylsilyl) amide in VI, XVIA, XVIB can be used for the alkylation defined above (when in Z1 or Z2). Palladium-catalyzed allyl can be used. Basic alkanes are fluorenyl or fluorenyl precursors (XXXVII, XXXIX, XL, (trimethylsilyl) sodium or amines), palladium catalysts (such as acetic acid esters (CH3C02CHrCH = CH4) Solvent (such as tetrahydrofuran) from 12 (reaction diagram XΠ) or —R11 — CVI, XVIA) or —R11 — (Please read the precautions on the back before filling out this page) The paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 486469 Printed by A7 __B7_ of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (58) 〇Pf (Reaction Diagram XVIB, Reaction Diagram X × ί). The product of this reaction contains the -R12 group or a R11 — X1 group (or a R11 — OPG group). The saturation of olefins in R11 or R12 can be accomplished by standard catalytic hydrogenation conditions. Reaction diagrams X m, X vi and X νπ The oxidation of sulfur in the system is as follows. Structures XXXVI, XXX, XXXDIE I9 sulfides can be selectively oxidized to ASUS by 1 mol equivalent reagents known in the art such as 30% hydrogen peroxide * sodium periodate, and peracids (such as meta-chloroperbenzoic acid). The obtained arsenic can be further converted into related masters by another molar equivalent or excess of 30% hydrogen peroxide, potassium permanganate, KHS05, or peracid (such as meta-chloroperbenzoic acid). .Also, it can be made directly from sulfides and 2 mol equivalents or more oxidants such as 30% hydrogen peroxide and peracids (such as meta-chloroperbenzoic acid). If an amine ( (Such as piperidine in I 9), the basic nitrogen can be protected by pretreatment with an acid such as hydrochloric acid or trifluoroacetic acid (see Reaction Diagram X IX). To prepare an example where Z1 or Z2 is a CHOH, Compounds in which Z1 or Z2 is C = 0, I, Ii, Π, and ni can be reduced with a hydride reagent such as sodium borohydride. The compounds of the present invention can be used to prevent, stabilize, or cause regression of mammalian atherosclerosis , Which is to reduce the M TP by administering an effective medical amount of the compound (Please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -61-486469 A7 ___B7_ V. Description of the invention (59) ( (Please read the notes on the back before filling this page.) The compounds of the present invention can use the procedures shown in US Patent Application Series No. 1 1 7, 3 6 2 published on September 3, 193, and use MTP isolated from one of the following sources to test MTP inhibitory activity: (1) microsomes of bovine liver, (2) Hep G 2 cells (human hepatoma cells) or (3) manifested in baculovirus Then combine human MT P. The present invention is also used to reduce mammalian serum fat concentrations, such as cholesterol or triglyceride (TG) concentrations, by reducing the activity of MT P by administering an effective medical amount of the compound. The compounds of the present invention can be used to treat a variety of other conditions or diseases that require treatment with a formulation that reduces MT activity. For example, the compounds of the present invention can reduce the amount or activity of MT P, and therefore can reduce serum cholesterol and triglyceride values, and thus are useful for treating hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, pancreatitis , Hyperglycemia and obesity. Printed by the Consumers' Cooperative of the Ministry of Economic Affairs of the Ministry of Economic Affairs, the compound of the present invention can reduce the MTP activity of the preparation, so it can be administered to various mammals in need of such treatment, such as monkeys, dogs, cats, mice, humans. These preparations can be administered systemically, such as orally or parenterally. Preparations that can reduce the activity or amount of MT P can be combined into conventional system dosage forms, such as tablets, capsules, elixirs, or injectable formulations. The above dosage forms also include the necessary physiologically acceptable carrier materials, excipients, Lubricants, buffers, antibacterials, bulking agents (such as mannitol), antioxidants (ascorbic acid or sodium bisulfite), etc. Oral formulations are ideal, but parenteral formulations are also quite satisfactory. This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -62-486469 A7 B7 V. Description of the invention (60) The dosage must be based on the patient's age, weight and condition, as well as the route of administration, dosage form And the camera method, and the desired results are carefully adjusted. Generally, the above dosage forms can be administered in single or discrete doses from about 5 to about 500 mg per day, one to four times daily. The following examples represent preferred embodiments of the present invention. Unless otherwise specified, all temperatures are in ° C. Example 9-[3-[4-((2,3-dihydrol-1, 1-oxyl-1H, oligomer 丨 late-2-yl) -1, 1-acryloyl] propyl] -N-propyl A 9 H —Stolen 9 —Metrazidine _____ (Please read the notes on the back before filling this page) A.

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

於氬下，於0°C下，先將催化量之二甲基甲醯胺（ 〇 · 5毫升），加至10克（45 · 57毫莫耳）9 一芴 羧酸（Aldrich)之8 0毫升二氯甲烷懸浮液中，繼而將 36毫升（71 . 35毫莫耳）草醯氯（2莫耳濃度之二 氯甲烷液）逐滴加入。而後將反應加溫至室溫，再攪拌 氏張尺度適用中國國家標準（CNS ) Μ規格（210X297公釐） -- 486469 A7 B7 五、發明説明（61 ) 4 5分蕕（反應變爲清澈之黃色溶液）’於此時將其蒸發 至乾，再於高度真空下泵唧〇·5小時。繼而令黃色餘留 物溶於5 0毫升二氯甲烷中，冷卻至〇°C，再以7 · 8毫 升（95 .14毫莫耳）丙胺逐滴處理（極具放熱性）， 繼而以7毫升吡啶處理以海綿吸收過量之氫氯酸。再將反 應固化，並以1 : 1二氯甲烷/水（200毫升）處理， 而後令之攪拌直至所有東西均成溶液爲止。將有機相以水 清洗（2次），乾燥（硫酸鈉），並予蒸發以得黃色固狀 物。由熱甲醇中結晶予以純化後，即得4 · 0克（33% )淡黃色固狀之標題化合物。 熔點· 1 9 8 - 2 0 0 °C。 (請先閱讀背面之注意事項再填寫本頁)Under argon at 0 ° C, a catalytic amount of dimethylformamide (0.5 ml) was first added to 10 g (45.57 mmol) of 9 hydrazone carboxylic acid (Aldrich). To 0 ml of a dichloromethane suspension, 36 ml (71.35 millimoles) of scopolamine (2 moles of dichloromethane solution) was added dropwise. Then the reaction was warmed to room temperature, and the scale of the stirrer was applied to the Chinese National Standard (CNS) M specification (210X297 mm)-486469 A7 B7 5. Description of the invention (61) 4 5 minutes (the reaction became clear Yellow solution) 'At this point it was evaporated to dryness and pumped under high vacuum for 0.5 h. The yellow residue was dissolved in 50 ml of dichloromethane, cooled to 0 ° C, and treated with 7.8 ml (95.14 mmol) of propylamine dropwise (very exothermic), followed by 7 The ml of pyridine was treated with a sponge to absorb excess hydrochloric acid. The reaction was solidified and treated with 1: 1 dichloromethane / water (200 ml), and then stirred until everything was in solution. The organic phase was washed with water (twice), dried (sodium sulfate), and pre-evaporated to obtain a yellow solid. After purification by crystallization from hot methanol, 4.0 g (33%) of the title compound was obtained as a pale yellow solid. Melting point · 198-2 0 ° C. (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 於氬下，於0°C下，先將10 · 5克（0 . 15莫耳 )咪唑，後將20 · 7克（0 · 14莫耳）特丁基二甲基 甲矽烷基氯加至49毫升（0 · 55莫耳）1 ，4 一丁二 醇之2 5毫升二甲基甲醯胺溶液中。再將反應徐緩加溫至 室溫，而後攪拌1 8小時，於此時將反應以乙醚稀釋並以 氯化銨水，碳酸鈉，鹽水清洗，並予乾燥（硫酸鎂）。所 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 64 486469 A7 ___ B7 _五、發明説明（62 ) 得液籐形式之無色標題化合物（5 0克）乃含有約1 5% 二甲矽烷基化之化合物。 B(2) ·The Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs printed under argon, at 0 ° C, first 10 · 5 g (0.15 Molar) of imidazole, and then 20.7 g (0 · 14 Molar) of tertin Dimethylsilyl chloride was added to a solution of 49 ml (0.55 mol) of 1,4-monobutylene glycol in 25 ml of dimethylformamide. The reaction was slowly warmed to room temperature and then stirred for 18 hours, at which time the reaction was diluted with ether and washed with ammonium chloride water, sodium carbonate, brine, and dried (magnesium sulfate). All paper dimensions are in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 64 486469 A7 ___ B7 _V. Description of the invention (62) The colorless title compound (50 g) in the form of liquid rattan contains about 15% Dimethylsilylated compounds. B (2) ·

於氬下，於0°c下，將7 · 3克（10 8毫莫耳）咪 唑及16 · 7克（64毫莫耳）三苯膦加至8 · 5克（ 42毫莫耳）第B (1)部化合物之50毫升四氫呋喃溶 液中。再將混合物攪拌4 5分鐘（溶液變爲均勻），並於 此時將16 · 2克（64毫莫耳）碘之50毫升四氫呋喃 液於2 0分鐘期間加入。而後將反應攪拌1小時，以己院 稀釋及以1莫耳濃度亞硫酸氫鈉，碳酸鈉，鹽水清洗，並 予乾燥（硫酸鈉）。將所得餘留物以乙醚碾磨（3次）， 過濾（以移去三苯膦化氧），再予蒸發，即得10克（ 61%)淡黃色油狀之標題化合物。 B(3)· (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝Under argon, add 7.3 g (108 mmol) of imidazole and 16.7 g (64 mmol) of triphenylphosphine to 0. 5 g (42 mmol) at 0 ° C. Part B (1) of the compound in 50 ml of tetrahydrofuran. The mixture was stirred for a further 4 5 minutes (the solution became homogeneous), and at this time, 16.2 g (64 mmol) of iodine in 50 ml of tetrahydrofuran was added over a period of 20 minutes. The reaction was then stirred for 1 hour, diluted with hexane and washed with 1 mole sodium bisulfite, sodium carbonate, brine, and dried (sodium sulfate). The resulting residue was triturated with ether (3 times), filtered (to remove triphenylphosphine oxide), and evaporated to give 10 g (61%) of the title compound as a pale yellow oil. B (3) · (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

於氬下，於0°C下，將960毫升（2 .40毫莫耳 )正丁基鋰（2 · 5莫耳濃度之己烷液）逐滴加至300 毫克（1 · 2毫莫耳）第A部化合物之1 〇毫升四氫呋喃 混合液中。再將所得橘色雙陰離子於0 °C下攪拌0 · 5小 時，並於此時將452毫克（1 · 44毫莫耳）第B (2 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469 A7 ___B7_____ 五、發明説明（63 ) )部化洽物逐滴加入。繼而將反應加溫至室溫，再攪拌 1 8小時，並於此時以1 : 1乙酸乙酯/水混合液處理， 而後將有機相乾燥（硫酸鈉），蒸發，於5 0克矽膠上並 以4;1己烷/乙酸乙酯洗提予以急驟色層分離，即得 4 6 0毫克（8 7%)淡黃色固狀之標題化合物。 c.Under argon at 0 ° C, 960 ml (2.40 mmol) of n-butyllithium (hexane at 2.5 moles) was added dropwise to 300 mg (1.2 mmol) ) 10 ml of tetrahydrofuran mixture of Part A compound. The obtained orange dianion was further stirred at 0 ° C for 0.5 hours, and at this time, 452 mg (1.44 mol) of No. B (2 paper size was applicable to China National Standard (CNS) A4 specifications ( 210X297 mm) 486469 A7 ___B7_____ V. Description of the invention (63)) The chemical compound is added dropwise. The reaction was then warmed to room temperature, stirred for another 18 hours, and then treated with a 1: 1 ethyl acetate / water mixture. The organic phase was then dried (sodium sulfate), evaporated, and placed on 50 g of silica gel. It was then extracted with 4: 1 hexane / ethyl acetate and separated by flash chromatography to obtain 460 mg (8 7%) of the title compound as a pale yellow solid. c.

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 將14 · 1毫升（14 · 10毫莫耳）1莫耳濃度四 丁銨化氟之四氫呋喃液加至5 · 6克（1 2 . 8 0毫莫耳 )第Β部化合物中。再將反應於氬下，於室溫下攪拌丄8 小時，並於此時以乙醚稀釋，及以氯化銨令反應中止。再 將有機相以水，鹽水清洗，並予乾燥（硫酸鈉）及蒸發。 而後於250克矽膠上使用95:5二氯甲烷/異丙醇洗 提予以急驟色層分離，即得4 · 09克（99%)白色固 狀之標題化合物。 熔點·了 3 - 7 5 °C。Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). 5.6 g (12.80 mmol) in Part B compound. The reaction was further stirred under argon at room temperature for 8 hours, at which point it was diluted with ether and the reaction was stopped with ammonium chloride. The organic phase was washed with water and brine, dried (sodium sulfate) and evaporated. Then, 250 g of silica gel was used to elute with 95: 5 dichloromethane / isopropanol and the color separation was performed rapidly to obtain 4.09 g (99%) of the title compound as a white solid. Melting point: 3-7 5 ° C.

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -66 - 486469 A7 __—_B7 五、發明説明（64 ) 於氬下，於0°C下，先將463毫克（6 ·81毫莫 耳）咪唑，後將1 · 0克（4 · 03毫莫耳）三苯膦加1 克（3 · 10毫莫耳）第C部化合物之20毫升四氫呋喃 溶液中。1 5分鐘後混合物變爲均勻，並於此時將1 . 〇 克（4·03毫莫耳）碘之20毫升四氫呋喃於20分鐘 期間逐滴加入。再將反應加溫至室溫，攪拌1小時，並於 此時以己烷稀釋，再將有機相以亞硫酸氫鈉，碳酸氫鈉， 鹽水清洗，並予乾燥（硫酸鈉）。而後於10 0克矽膠上 以1 : 1己烷/乙酸乙酯洗提予以急驟色層分離，即得 1 · 1克（85%)無色油狀之標題化合物。 Ε· 2 —〔1一（苯甲基）一 4一哌啶基〕一1Η —異 口㈣一 1 ，3 ( 2 Η )-二酮 經濟部中夬標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 邊攪拌邊將酞酸酐（15·0克，101毫莫耳）及 4 一胺基一 1—爷基哌B定（19 · 3克，101毫莫耳） 之混合物於油浴中加熱直至混合物熔化爲止（約1 2 5°c )。再令反應保持於此溫度下直至混合物再度固化爲止（ 約30分鐘）。繼而將反應冷卻至室溫。再於1公斤矽膠 上進行急驟色層分離，並以3 0%乙酸乙酯之己烷液予以 負載及洗提而予以純化。再結合純溶離份，並予蒸發，即 得白色固狀之化合物A (25克，77%)，熔點15 1 一 1 5 4 °C。 F · 2 ，3 —二氫基一 2 —〔1 一（苯甲基）一 4 一哌 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X 297公釐） -67 - 486469 A7 B7 五、發明説明（65 ) t基Γ’一 1 Η -異吲跄一 1 酮 於氬下，將鋅粉（28 · 6克，438毫莫耳）加至 化合物E (20 · 0克，62 · 5毫莫耳）之乙酸（ 2 4 8毫升）溶液中。邊機械攪拌，邊令反應迴流過夜。 繼而令反應通過Celite®中過濾，再蒸發至乾。而後將二 氯甲烷（5 00毫升）加入，將有機層以飽和碳酸氫鈉（ 2X100毫升），鹽水（100毫升）清洗，再於硫酸 鎂上乾燥。蒸發後可得粗製油狀物。將所得餘留物與甲苯 (2 X 3 0毫升）共沸以得白色固狀物，繼而將產物由異 丙醇中予以再結晶，即得白色固狀之化合物B ( 1 6克， 8 0%)(熔點 130-133 °C)。 G · 2- (4 -哌啶基）—2，3-二氫基-1H-異 口引跺一 1 一酮_ (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 於氬下，先將乙酸（3 · 5毫升，52 .8毫莫耳） ’後將10%鈀/活性碳（0 · 7克）加至第F部化合物 (8 · 5克，26 · 4毫莫耳）之乙醇（65毫升）溶液 中。再將漿狀物以氮氣淨化，而後於45ps i氫氣壓下 攪動4 8小時。繼而令反應通過Celite®中過濾，並以乙 醇清洗。而後將濾液蒸發至乾。令所得餘留物溶於氯仿（ 1 0 0毫升）中，及以1當量濃度已以氯化鈉飽和之氫氧 化鉀清洗（2x30毫升），並於硫酸鎂上乾燥。再將所 得清澈溶液蒸發至乾，與甲苯（2 X 3 0毫升）共沸，艮口 得白色固狀之化合物G (5 · 0克，77%)， 本紙張又度適用中國國家標準（CNS ) Α4規格（210X297公釐） -68 - 486469 Α7 Β7 五、發明説明（66 ) 熔點厂1This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -66-486469 A7 __—_ B7 V. Description of the invention (64) Under argon, at 0 ° C, first 463 mg (6 · 81 Millimoles) imidazole, then 1.0 grams (4.03 millimoles) of triphenylphosphine was added to a solution of 20 grams of tetrahydrofuran (1.10 millimoles) of Part C compound. After 15 minutes, the mixture became homogeneous, at which point 1.0 g (4.03 mmol) of iodine in 20 ml of tetrahydrofuran was added dropwise over a period of 20 minutes. The reaction was warmed to room temperature, stirred for 1 hour, and then diluted with hexane. The organic phase was washed with sodium bisulfite, sodium bicarbonate, brine, and dried (sodium sulfate). Then, 100 g of silica gel was eluted with 1: 1 hexane / ethyl acetate and separated by flash chromatography to obtain 1.1 g (85%) of the title compound as a colorless oil. Ε · 2 — [1- (benzyl) -4-piperidinyl] —1Η—Isobutene-1, 3 (2Η) -dione Printed by the Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Affairs (please first Read the notes on the reverse side and fill in this page) While stirring, mix the phthalic anhydride (15.0 g, 101 mmol) and 4-monoamino-1-dipyridine B (19 · 3 g, 101 mmol) ) The mixture is heated in an oil bath until the mixture is melted (approximately 125 ° C). The reaction was kept at this temperature until the mixture was cured again (about 30 minutes). The reaction was then cooled to room temperature. It was then separated on 1 kg of silica gel by flash chromatography, and purified by loading and eluting with 30% ethyl acetate in hexane. Combine the pure soluble fractions and pre-evaporate to obtain Compound A (25 g, 77%) as a white solid with a melting point of 15 1 to 15 4 ° C. F · 2, 3 -dihydro-1-2-[1-(benzyl)-4-1 pipe This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) -67-486469 A7 B7 5 2. Description of the invention (65) T-based Γ′- 1 Η-isoindene- 1 ketone under argon, zinc powder (28.6 g, 438 mmol) was added to compound E (20.0 g, 62 · 5 mmol) in acetic acid (248 ml). While mechanically stirring, the reaction was refluxed overnight. The reaction was then filtered through Celite® and evaporated to dryness. Dichloromethane (500 ml) was then added, and the organic layer was washed with saturated sodium bicarbonate (2 × 100 ml), brine (100 ml), and dried over magnesium sulfate. After evaporation, a crude oil was obtained. The obtained residue was azeotroped with toluene (2 × 30 ml) to obtain a white solid, and then the product was recrystallized from isopropanol to obtain a white solid Compound B (16 g, 80). %) (Melting point 130-133 ° C). G · 2- (4-piperidinyl) -2,3-dihydro-1H-isobutyrin-1 1-one_ (Please read the precautions on the back before filling this page) Staff of the Central Bureau of Standards, Ministry of Economic Affairs The consumer cooperative was printed under argon, and acetic acid (3.5 ml, 52.8 mmol) was added to the F-part compound (8.5 g) after adding 10% palladium / activated carbon (0.7 g). , 26.4 mmol) in ethanol (65 ml). The slurry was purged with nitrogen and stirred at 45 ps i of hydrogen pressure for 48 hours. The reaction was then filtered through Celite® and washed with ethanol. The filtrate was then evaporated to dryness. The resulting residue was dissolved in chloroform (100 ml), washed with 1 equivalent of potassium hydroxide saturated with sodium chloride (2 x 30 ml), and dried over magnesium sulfate. The resulting clear solution was evaporated to dryness and azeotroped with toluene (2 x 300 ml). Compound G (5.0 g, 77%) was obtained as a white solid. This paper was also adapted to Chinese national standards (CNS ) Α4 specifications (210X297 mm) -68-486469 Α7 Β7 V. Description of the invention (66) Melting point factory 1

7 — 1 4 0 0C Η · 9 -〔3 -〔4 一（2，3 -二氫基一 1 一 合氧基 —1Η -異朵一 2 -基）一 1 一哌啶基〕丙基〕—Ν — 丙某一 QH —芴一 9 一甲醯胺_— —___ 於氬下，於室溫下，先將210毫克（1 . 5 2毫莫 耳）碳酸鉀，後將198毫克（0 · 76毫莫耳）第G部 化合物加至3 3 0毫克（0 · 7 6毫莫耳）第d部化合物 之5毫升二甲基甲醯胺溶液中。再將混合物於室溫下攪拌 7 2小時，並於此時將反應以乙醚稀釋，以水，鹽水清洗 ’乾燥（硫酸鈉）及蒸發。由熱己烷中予以再結晶後，即 得270毫克（68%)白色固狀之標題化合物。 熔點· 1 3 6 — 1 3 8 °C。 分析· C34H39N302之計算值： C，78.28;H，7.53;N，8.05 實測值：C ，7 8 ，1 1 ; Η，7 · 6 2 ; N，8 · 0 9 (請先閲讀背面之注意事項再填寫本頁) 衣·7 — 1 4 0 0C Η · 9-[3-[4 mono (2,3 -dihydrol-1 1-oxyl-1Η-isotope-2 -yl) -1 1 piperidinyl] propyl] —N — Propionate QH — 芴 -9 monomethylamine _ — — ___ Under argon at room temperature, first 210 mg (1.5 2 mmol) potassium carbonate, then 198 mg (0 · 76 millimoles) of the compound in part G was added to a solution of 330 mg (0.676 millimoles) of the compound in part d in 5 ml of dimethylformamide. The mixture was further stirred at room temperature for 72 hours, at which time the reaction was diluted with ether, washed with water, brine ', dried (sodium sulfate) and evaporated. After recrystallization from hot hexane, 270 mg (68%) of the title compound was obtained as a white solid. Melting point · 1 3 6 — 1 3 8 ° C. Analysis · Calculated value of C34H39N302: C, 78.28; H, 7.53; N, 8.05 Found: C, 7 8, 1 1; Η, 7 · 6 2; N, 8 · 0 9 (Please read the precautions on the back first (Fill in this page again)

、1T 經濟部中央標準局員工消費合作杜印製 實例1 A 复例3 1 0氣氯酸鹽之另一種合成法 將1 0 %鈀/活性碳（1 · 2克）加至實例5游離胺 (12克，23 ·1毫莫耳）之無水乙醇（400毫升） 溶液中。再將混合物於帕爾儀器上，於40ps i下氫化 2小時，而後通過寅氏鹽中過濾。繼而將濾液於真空中濃 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 一 69 一 486469 經濟部中央標率局員工消費合作社印製 A7 B7五、發明説明（67 ) 縮以得‘無色油狀物。再令產物溶於甲醇（1 0 0毫升）中 ，而後將1 . 0莫耳濃度氫氯酸之乙醚液（20毫升， 2 0毫莫耳）逐滴加入，再將反應攪拌1 0分鐘，繼而於 真空中濃縮。將餘留物置於乙睛（2毫升）中，再將水（ 2 5毫升）加入。繼而將略混濁之溶液低壓凍乾過夜，即 得白色低壓凍乾狀之標題化合物（11 .1克，86%) 〇 分析· C34H39N3〇2e 1 . 3HC 芡· 1 · 6H2〇之 理論值： C，6 8 · 2 4 ; Η，7 · 3 3 ; N，7 · 0 2 ;C 芡，7 · 7 6 實測值：C，6 8 · 2 7 ; Η，7 · 3 1 ; Ν，6 · 9 9 ' C 殳，Ί · Ί Ί。 實例2 2，3 —二氫基一 2 —〔1—〔4 一合氧基一 4— (9 — 丙基一 9Η -荀一 9 —基）丁基〕一 4 一呢Β定基〕一 1Η 一異呻跺_ 1 -酮，單氫氯酸鹽_ (請先閱讀背面之注意事項再填寫本頁)、 1T Consumption cooperation between employees of the Central Bureau of Standards, Ministry of Economic Affairs, Du printed example 1 A Duplicate example 3 1 0 Another synthesis method of chlorate Added 10% palladium / activated carbon (1.2 grams) to Example 5 free amine (12 g, 23.1 mmol) in absolute ethanol (400 ml). The mixture was then hydrogenated on a Parr apparatus at 40 ps for 2 hours, and then filtered through Yin's salt. Then the filtrate was concentrated in a vacuum. The paper size was applied to the Chinese National Standard (CNS) A4 specification (210 × 297 mm). 69.486469. Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. A7 B7. It's a colorless oil. The product was dissolved in methanol (100 ml), and then 1.0 mol of hydrochloric acid in diethyl ether (20 ml, 20 mmol) was added dropwise, and the reaction was stirred for 10 minutes. It was then concentrated in vacuo. Place the residue in acetone (2 ml) and add water (25 ml). The slightly turbid solution was then lyophilized overnight to obtain the title compound (11.1 g, 86%) as a white lyophilized product. 〇 Analytical · C34H39N3〇2e 1. 3HC 芡 · 1 · 6H2〇 Theoretical value: C , 6 8 · 2 4; Η, 7 · 3 3; N, 7 · 0 2; C 芡, 7 · 7 6 Found: C, 6 8 · 2 7; Η, 7 · 3 1; Ν, 6 · 9 9 'C 殳, Ί · Ί Ί. Example 2 2,3-Dihydrol-2— [1— [4-Hydroxy-1—4- (9-propyl-9′-fluorene-9-yl) butyl] −4−N-butyl aridyl] —1Η Isoamidine _ 1 -one, monohydrochloride _ (Please read the precautions on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） -70 - 486469 A7 _ B7 五、發明説明（68 ) 於‘一 20 °C下，於氬下，將10 1毫升（303毫莫 耳）3·0莫耳濃度甲基鎂化氯之四氫呋喃於20分鐘期 間逐滴加至已攪拌之28 · 55克（301 · 9毫莫耳） 3 —氯基一 1 —丙院（Aldrich)之3 0 0毫升四氫映喃 溶液中。於一 2 0 °C下0 · 5小時後，令反應加溫至室溫 ，再將1 1 · 0克（452 · 8毫莫耳）鎂屑加入，繼而 令反應加熱至迴流。於迴流之初，將0 · 60毫升（ 6 · 9 4毫莫耳）1，2 -二溴乙烷加入，於迴流下1小 時後，再將另〇 · 6 0毫升加入。於迴流下2小時後，令 反應冷卻至室溫。 (請先閲讀背面之注意事項再填寫本頁)This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -70-486469 A7 _ B7 V. Description of the invention (68) At -20 ° C, under argon, put 10 1 ml (303 milliliter) Mole) 3.0 Molar concentration of tetrahydrofuran with methylmagnesium chloride was added dropwise over a period of 20 minutes to the stirred 28.55 g (301.9 mmol) of 3-chloro- 1-C ) In 300 ml of tetrahydroimran solution. After 0.5 hours at 20 ° C, the reaction was allowed to warm to room temperature, and 11.0 grams (452.8 millimoles) of magnesium dust was added, and the reaction was heated to reflux. At the beginning of reflux, add 0.60 ml (6.49 mol) of 1,2-dibromoethane, and after 1 hour at reflux, add another 0.60 ml. After 2 hours at reflux, the reaction was allowed to cool to room temperature. (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 B(1)·9一丙基一9H—荀一9一羯酸Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

於氬氣層下，將9 一芴羧酸（12克，57毫莫耳） 之2 5 0毫升四氫呋喃溶液冷卻至〇°C，再將2當量（ 71 · 25毫升）1 · 6莫耳濃度正丁基鋰之己烷溶液及 正丙基碘（7 · 5毫升，13 · 1克，77毫莫耳）先後 本紙張尺度適用中國國家標準（CNS) A4規格（2i〇x297公釐） 486469 A7 _____B7 五、發明説明（69 j 加入〃而後將反應混合物於0 °C下攪捽6小時。將另1毫 升正丙基碘加入，再將反應於0°C下攪拌4小時。繼而藉 加入7 5毫升水以令反應中止，再使用3當量濃度氫氯酸 以調整p Η至1，而後將反應混合物以己烷萃取（ 3 X 2 0 0毫升），再將己烷萃取液以水，鹽水清洗，並 於無水硫酸鈉上乾燥。而後將溶劑蒸發以得黃色油狀之粗 製產物，令之溶於約2 5 0毫升乙醇中，於迴流下以 Darco G-60加熱，通過寅氏鹽中過濾，再濃縮成約原始量 之一半。繼而將水徐緩加入直至混合物變爲混濁爲止，而 後將混合物再加熱，再令之徐緩冷卻至室溫，即得 10 · 5克（73%)無色晶狀之標題化合物。 熔點· 120 - 122 °C。 B(2). (請先閲讀背面之注意事項再填寫本頁)Under an argon layer, cool 250 ml of a solution of 9 monoammonium carboxylic acid (12 g, 57 mmoles) in tetrahydrofuran to 0 ° C, and then reduce 2 equivalents (71.25 ml) of 1.6 moles. N-Butyllithium in hexane solution and n-propyl iodide (7.5 ml, 13.1 g, 77 mmol) successively. This paper size applies the Chinese National Standard (CNS) A4 specification (2i0x297 mm) 486469 A7 _____B7 V. Description of the invention (69 j Add 〃 and stir the reaction mixture at 0 ° C for 6 hours. Add another 1 ml of n-propyl iodide, and then stir the reaction at 0 ° C for 4 hours. Then add by 7 5 ml of water to stop the reaction, and then use 3 equivalents of hydrochloric acid to adjust p Η to 1, and then extract the reaction mixture with hexane (3 x 2000 ml), and then extract the hexane extract with water. It was washed with brine and dried over anhydrous sodium sulfate. Then the solvent was evaporated to obtain the crude product as a yellow oil, which was dissolved in about 250 ml of ethanol, heated under reflux with Darco G-60, and passed through Yin's salt. Medium filtration, and then concentrated to about half of the original amount. Then slowly add water until the mixture becomes mixed So far, the mixture was reheated and allowed to slowly cool to room temperature to obtain 10.5 g (73%) of the title compound as colorless crystals. Melting point: 120-122 ° C. B (2). (Please first (Read the notes on the back and fill out this page)

經濟部中央標準局員工消費合作社印裝 將草醯氯（4 · 5毫升，8 · 93毫莫耳）於5分鐘 期間加至第B (1)部化合物之二氯甲烷（10毫升，含 2滴二甲基甲醯胺）溶液中。再將反應於室溫下攪拌2小 時，而後於真空中濃縮，即得1.6克暗黃色固狀之粗製 醯基氯。 本紙張尺度適用中國國家標準（CNS ) A4規格（210x297公釐）一72 486469 A7 B7 五、發明説明（70 )Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Chlorchlor (4.5 ml, 8.93 mmol) was added to the compound of Part B (1) in dichloromethane (10 ml. Drop of dimethylformamide) solution. The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo to obtain 1.6 g of crude fluorenyl chloride as a dark yellow solid. This paper size applies to Chinese National Standard (CNS) A4 size (210x297 mm)-72 486469 A7 B7 V. Description of invention (70)

(請先閲讀背面之注意事項再填寫本頁) 於氬下，將第B部化合物（1 · 07克，3 · 97毫 莫耳）之四氫呋喃（1 0毫升）溶液冷卻至0 °C，再將碘 化銅（I) (38毫克，0.20毫莫耳）加入，繼而將 第A部化合物（14 . 5毫升，0 · 3莫耳濃度之四氫呋 喃液，4 · 3 7毫莫耳）於1 0分鐘期間逐滴加入。加入 後，出現深紅色，但隨攪拌而快速消失。將不透明之黃色 反應於0°C下攪拌4 5分鐘，而後藉加入飽和氯化銨（ 經濟部中央標準局員工消費合作社印製 1 0毫升）以令反應中止—將反應以水（1 0毫升）稀釋 ’並以乙酸乙酯萃取（3x30毫升）。再將結合之有機 層以飽和氯化銨，水及鹽水（各1 0毫升）清洗，繼而於 硫酸鎂上乾燥。蒸發後可得1 · 3克黃色油狀物，再藉於 矽膠（1 5 0克）上進行急驟色層分離，裝填於5 0%乙 酸乙酯/己烷中，以2 5%乙酸乙酯/己烷洗提而予以純 化，即得無色油狀之標題化合物（8 8 5毫克，7 6%)(Please read the precautions on the back before filling this page) Under argon, cool the tetrahydrofuran (10 ml) solution of Part B compound (1.07 g, 3.97 mmol) to 0 ° C, and then Copper (I) iodide (38 mg, 0.20 mmol) was added, followed by Part A compound (14.5 ml, tetrahydrofuran solution at a concentration of 0.3 mole, 4.37 mmol) Added dropwise over 0 minutes. After the addition, a dark red color appeared, but quickly disappeared with stirring. The opaque yellow reaction was stirred at 0 ° C for 4 5 minutes, and then the reaction was stopped by adding saturated ammonium chloride (printed by 10 ml of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs)-the reaction was water (10 ml ) Diluted 'and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with saturated ammonium chloride, water and brine (10 ml each), and then dried over magnesium sulfate. After evaporation, 1.3 g of yellow oil was obtained, which was then separated by flash chromatography on silica gel (150 g), filled with 50% ethyl acetate / hexane, and 25% ethyl acetate. / Hexane extraction and purification to give the title compound as a colorless oil (888 mg, 7 6%)

於0°C下，於氬下，將n -溴基琥珀醯亞胺（4 3 1 本紙張又度適用中國國家標準（CNS ) Μ規格（210X297公着） -73 - 486469 A7 B7 五、發明説明（71 ) (請先閱讀背面之注意事項再填寫本頁) 毫克，. 42毫莫耳）加至第C部化合物（ 6 47毫克 ，2 · 20毫莫耳）及三苯膦（634毫克，2 · 42毫 莫耳）之二氯甲烷（7毫升）溶液中。再將反應於〇°C下 攪拌1小時，以二氯甲烷（2 0毫升）稀釋，以1 〇 %水 性亞硫酸鉀（5毫升），水（5毫升）及鹽水（5毫升） 清洗，而後於硫酸鎂上乾燥。繼而將混合物過濾，再將矽 膠（3克）加至濾液中。蒸發後可得綠色粉末，再將之藉 於矽膠上（5 0克）進行急驟色層分離並以3 0%二氯甲 烷/己烷洗提而予以純化，即得無色油狀之標題化合物（ 733毫克，93%)。 E . 2，3 —二氫基一 2 —〔 1 一〔4 一合氧基一 4 一 (9 —丙基一 9H -芴一 9 一基）丁基〕一 4 一哌啶基〕 —1 Η -異口引口朵一 1 一酮，單氣氛酸鹽__ 經濟部中央標準局員工消費合作社印製 將第D部化合物（336毫克，0 · 94 1毫莫耳） 及實例1第G部化合物（22 5毫克，1 · 04毫莫耳） 之無水乙醇（3毫升）溶液於氬下迴流過夜（2 0小時） ，再冷卻至室溫，此時有白色固狀物沈澱出。將混合物於 真空中濃縮，再令所得餘留物分界於乙酸乙酯（2 0毫升 )及飽和碳酸氫鈉（1 0毫升）間。而後將有機層以水（ 5毫升）及鹽水（5毫升）清洗，於硫酸鈉上乾燥。蒸發 後可得4 1 5毫克無色油狀物，再將之藉於矽膠上（5 0 克）進行急驟色層分離並以2 5%丙酮/二氯甲烷洗提而 予以純化，以得2 0 5毫克無色油狀之期望游離胺。 本紙張尺度適用中國國家標準（CNS ) Α4規格（21〇Χ：297公釐） -74 - 486469 經濟部中央標準局員工消費合作社印製 A7 ___^_ B7______ 五、發明説明（72 ) 將當量濃度氫氯酸/乙醚（3毫升，3毫莫耳）加 至以上所製胺之乙醚（3毫升）溶液中。再將含膠黏固狀 物之混合物於真空中濃縮以得膠黏玻璃狀物。令產物溶於 異丙醇（2毫升）中，再將己烷（1 5毫升）加入以令產 物沈澱。而後將混合物於真空中濃縮以得泡沫固狀物，將 其於6 0°C下，於高度真空下乾燥過夜，即得白色泡沬狀 之標題化合物（206毫克，41%)。 分析· C33H37C $ Ν2〇2· H2〇之計算值： C，7 2 · 2 7 ; Η，7 . 1 9 ; N，5 · 1 1 ;C 芡，6 · 4 6 實測值：C，了 2 · 3 6 ; Η，7 · 2 1 ; Ν，5 · 0 2 ;C 又，6 · 5 9 ° 賨例3 (Ε) — 9 —〔4 一〔4 一（1 ，3 —二氫基一 1 一合氧 基一 2 Η -異吲跺一 2 -基）一 1 一哌啶基〕一 2 -丁烯 基一 2，7 —二氟基一 Ν —（2，2，2 —三氟乙基）一 9Η —芴一 9 一甲醯胺____ ---------^^衣-- (請先閲讀背面之注意事項再填寫本頁) 訂 〇At 0 ° C, under argon, the n-bromosuccinimide (4 3 1 paper is again applicable to the Chinese National Standard (CNS) M specifications (210X297) -73-486469 A7 B7 V. Invention Instructions (71) (please read the precautions on the back before filling out this page) mg, .42 mmol) added to the compound of Part C (6 47 mg, 2.20 mmol) and triphenylphosphine (634 mg , 2.42 millimoles) in dichloromethane (7 ml). The reaction was stirred at 0 ° C for 1 hour, diluted with dichloromethane (20 ml), washed with 10% aqueous potassium sulfite (5 ml), water (5 ml) and brine (5 ml), and then Dry over magnesium sulfate. The mixture was then filtered, and silica gel (3 g) was added to the filtrate. After evaporation, a green powder was obtained, which was then purified by flash chromatography on silica gel (50 g) and purified by extraction with 30% dichloromethane / hexane to obtain the title compound as a colorless oil ( 733 mg, 93%). E. 2,3-Dihydrol-2— [1- [4-Hydroxy-4- (9-propyl-9H-fluorene-9-yl) butyl] -4 4-piperidinyl] —1 Η -Issue 1-one ketone, mono-aqueous acid salt __ Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Part D Compounds (336 mg, 0.94 1 mmol) and Example 1 G A solution of the compound (225 mg, 1.04 mmol) in absolute ethanol (3 ml) was refluxed under argon overnight (20 hours), and then cooled to room temperature, at which time a white solid precipitated. The mixture was concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL). The organic layer was then washed with water (5 ml) and brine (5 ml) and dried over sodium sulfate. After evaporation, 4 15 mg of a colorless oil was obtained, which was then purified by flash chromatography on silica gel (50 g) and purified by extraction with 2 5% acetone / dichloromethane to obtain 20 5 mg of the desired free amine as a colorless oil. This paper size applies the Chinese National Standard (CNS) A4 specification (21〇 ×: 297mm) -74-486469 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___ ^ _ B7______ 5. Description of the invention (72) The equivalent concentration Hydrochloric acid / diethyl ether (3 ml, 3 mmol) was added to a diethyl ether (3 ml) solution of the amine prepared above. The mixture containing the glue-like substance was concentrated in vacuo to obtain a gluey glass. The product was dissolved in isopropanol (2 ml) and hexane (15 ml) was added to precipitate the product. The mixture was then concentrated in vacuo to give a foamy solid, which was dried at 60 ° C under high vacuum overnight to give the title compound (206 mg, 41%) as a white foam. Analysis · Calculated values of C33H37C $ Ν2〇2 · H2〇: C, 7 2 · 2 7; Η, 7. 1 9; N, 5 · 1 1; C 芡, 6 · 4 6 Measured value: C, 2 · 3 6; Η, 7 · 2 1; Ν, 5 · 0 2; C again, 6 · 5 9 ° 賨 Example 3 (Ε) — 9 — [4 1 [4 1 (1, 3 —dihydrol — 1-Hydroxy- 2 fluorene-isoindio- 2 -yl)-1 -piperidinyl]-2 -butenyl-2,7 -difluoro -N-(2,2,2 -trifluoro (Ethyl)-9Η — 芴 -9 9-methylamine ____ --------- ^^ clothing-(Please read the precautions on the back before filling this page) Order 〇

本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）—75 - 486469 A7 B7 五、發明説明（73 ) A·The size of this paper applies to Chinese National Standard (CNS) A4 specification (210X297 mm)-75-486469 A7 B7 V. Description of invention (73) A ·

經濟部中央標準局員工消費合作社印製 於氬下，於一 10 °c 1 · 13 莫耳，48 - 5 Aldrich) (7 · 17克 (2 5毫升）懸浮液中。 物之形成而變得困難，然 均變爲溶液。而後將飽和 1 1毫升液，0 · 1 0 3 混合物過濾，以5 %水性 再將收集之固狀物於過濾 狀物乃用於接續之反應中 令上述固狀物懸浮於 熱至1 1 0 °C 2小時，同 流另2小時。繼而將溶液 出，再於高度真空下移去 7.5克）。將固狀物由 題化合物。繼而將黑色焦 於真空中濃縮。油狀一固 色層分離法（氧化矽，9 2 .5%乙酸乙酯：己烷 固狀之標題化合物（2. 產率）。 下將水性氟硼酸（7 1毫升， 0%)加至2，7 —二胺基芴（ 0· 036莫耳）之四氫呋喃 快加完之時，攪拌作用由於固狀 而酸完全加完後，大多數之固體 水性亞硝酸鈉溶液（7 . 1克之 莫耳）加入，1 · 5小時後，將 氟硼酸，甲醚，而後乙醚清洗， 燒瓶上約略乾燥。所得之棕色固 二甲苯 時觀察 由反應 揮發物 熱乙醇 油之乙 狀餘留 X 1 6 先後洗 4 4克 (10 到氣體 燒瓶中 以得暗 中結晶 醚清洗 物（4 公分） 提而予 ，共3 0毫升 釋出， 之黑色 褐色固 以得無 液與母 • 3克 ，以己 以純化 .8 4 )中，再加 而後令之迴 焦油中潷析 狀物（ 色固狀之標 液結合，再 )乃藉急驟 烷而後 ，即得無色 克，5 2 %The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs is printed under argon at a temperature of 10 ° C 1 · 13 Mor, 48-5 Aldrich (7 · 17 g (2 5 ml) suspension. The formation of the substance becomes Difficult, but all turned into solutions. Then the mixture of saturated 11 ml of liquid and 0 · 103 was filtered, and the collected solids were filtered in 5% water for subsequent reaction to make the above solids. The material was suspended in heat to 110 ° C for 2 hours, and co-current for another 2 hours. The solution was then removed and 7.5 g was removed under high vacuum). Remove the solid from the title compound. The black coke was then concentrated in vacuo. Oily-fixed layer separation method (silica, 9 2 .5% ethyl acetate: hexane as the title compound (2. Yield). Aqueous fluoboric acid (71 ml, 0%) was added to When tetrahydrofuran of 2,7-diaminopyrene (0.036 mol) was added shortly, most of the solid aqueous sodium nitrite solution (7.1 g of mol Ear), 1.5 hours later, the fluoroboric acid, methyl ether, and then ether were washed, and the flask was slightly dried. The obtained brown solid xylene was observed by the reaction of the volatile matter, hot ethanol oil, and the remaining X 1 6 successively. Wash 4 4 g (10 into a gas flask to obtain the dark crystalline ether washings (4 cm), which is released in a total of 30 ml. The black-brown solid is obtained as a liquid and the mother • 3 g, purified by yourself .8 4), and then add back the decanted matter (color solid standard solution in tar, and then) by the rapid alkane to obtain colorless gram, 5 2%

In 111111 11 (請先閲讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） -76 - 486469 A7 _______B7 五、發明説明（74 )In 111111 11 (Please read the notes on the back before filling out this page) The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) -76-486469 A7 _______B7 V. Description of the Invention (74)

於一 5°C下（冰/鹽水浴），於氬下，將正丁基鋰（ 3 . 4毫升，8 · 50毫莫耳，2 . 5莫耳濃度之己烷液 )逐滴加至第A部化合物（1 . 38克，6 · 82毫莫耳 )之四氫呋喃（15毫升）溶液中。1。15小時後，將 碎固狀二氧化碳（過量）加入，繼而將乙醚（約5毫升） 加入，再令反應於室溫下攪拌1 9小時β將棕色反應混合 物冷卻至0°C，加入2當量濃度氫氯酸令反應中止，再將 水性層以乙酸乙酯萃取兩次。繼而將結合之有機相於硫酸 鈉上乾燥，並於真空中蒸發以得適於供下一步驟用之無色 固狀之粗製標題化合物（1· 6 4克）。以己烷進行碾磨 則可移除未反應之初始物質第A部化合物。 C·At 5 ° C (ice / brine bath), under argon, n-butyllithium (3.4 ml, 8.50 millimolar, 2.5 mol hexane solution) was added dropwise to Part A compound (1.38 g, 6.82 mmol) in tetrahydrofuran (15 ml). After 1.15 hours, add crushed solid carbon dioxide (excess), then add diethyl ether (about 5 ml), and allow the reaction to stir at room temperature for 19 hours. The reaction was stopped by the equivalent concentration of hydrochloric acid, and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were then dried over sodium sulfate and evaporated in vacuo to give the crude title compound (1.64 g) as a colorless solid suitable for the next step. Milling with hexane removes the unreacted part A of the starting material. C ·

經濟部中央標準局員工消費合作社印策 (請先閱讀背面之注意事項再填寫本頁) 於氬氣層下，將第B部化合物（2，7 -二氟芴一 9 一羧酸）（500毫克，2 .05毫莫耳）之5毫升四氫 呋喃溶液冷卻至—30 °C，再將2當量2 · 5莫耳濃度正 丁基鋰之己烷溶液（1 · 64毫升，4. 1毫莫耳）加入 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐) ~ ~ 一 Π 一 486469 A7 B7 五、發明説明（75 ) 。而摄將混合物於一 30 °C下攪拌5分鐘，繼而加至1 ， 4 一二溴基一 2 -丁嫌（2 · 1 4克，1 〇毫莫耳）之4 毫升四氫呋喃冷（一 3 0°C)溶液中。再將反應混合物於 一 30 °C下攪拌30分鐘，而後使用1當量濃度氫氯酸令 反應中止，再以乙酸乙酯（3x10毫升）萃取。將乙酸 乙酯萃取液以水，鹽水清洗，及於無水硫酸鈉上乾燥。再 將粗製物質於Merck砂膠柱上以5 %異丙醇/二氯甲院洗 提而予以純化，即得4 8 0毫克（6 2%)無色固狀之標 題化合物，熔點142 — 146 °C。 (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Under the argon layer, place the compound of Part B (2,7 -difluorofluorene-9 monocarboxylic acid) (500 Mg, 2.05 mmol) of 5 ml of tetrahydrofuran solution was cooled to -30 ° C, and 2 equivalents of 2.5 mmol of n-butyl lithium in hexane solution (1.64 ml, 4.1 mmol) (Ears) added to this paper standard applicable to China National Standard (CNS) A4 specifications (210X297 mm) ~ ~ Π 486469 A7 B7 V. Description of the invention (75). The mixture was stirred at-30 ° C for 5 minutes, and then added to 1,4-dibromo-2-butane (2.14 g, 100 mmol) in 4 ml of tetrahydrofuran cold (-1 3 0 ° C) in solution. The reaction mixture was stirred at-30 ° C for 30 minutes, then the reaction was stopped with 1 equivalent of hydrochloric acid, and extracted with ethyl acetate (3 x 10 ml). The ethyl acetate extract was washed with water, brine, and dried over anhydrous sodium sulfate. The crude material was purified on a Merck gel column with 5% isopropanol / dichloromethane to obtain 480 mg (62%) of the title compound as a colorless solid, mp 142-146 ° C. (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 令第C部羧酸（465毫克，1 · 23毫莫耳）溶於 1 0毫升二氯甲烷中，再將二甲基甲孽胺（5 0毫升）加 入。而後將混合物於氬氣層下冷卻至0°C，再將草醯氯（ 165毫克，1·3毫莫耳）加入，而後令混合物加溫至 室溫，並攪拌2·5小時，繼而將混合物由二氯甲烷中蒸 發數次，以得淡黃色固狀之粗製醯基氯。 令醯基氯溶於5毫升四氫呋喃中，再於氬氣層下冷卻 至0°C。將三乙胺（142毫克，1.4毫莫耳），繼而 將2，2，2 —三氟乙胺（139毫克，1 . 4毫莫耳） 。而後令反應加溫至室溫並攪拌過夜。再藉加入飽和碳酸 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X297公釐） -78 - 486469 A7 B7五、發明説明（76 ) 氫鈉令應中止，並以乙酸乙酯（3x20毫升）萃取。 繼而將粗製產物藉於Merck EM矽膠柱上以1 0%乙酸乙醋 /己烷洗提而予以純化，即得2 3 0毫克（3 8 % )淡黃 色固狀之標題化合物。Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Part C of carboxylic acid (465 mg, 1.23 mmol) was dissolved in 10 ml of dichloromethane, and then dimethylmethanamine (50 ml) Join. Then the mixture was cooled to 0 ° C under an argon layer, and then chlorchloride (165 mg, 1.3 millimoles) was added, and then the mixture was warmed to room temperature and stirred for 2.5 hours, and then The mixture was evaporated several times from dichloromethane to give crude fluorenyl chloride as a pale yellow solid. The fluorenyl chloride was dissolved in 5 ml of tetrahydrofuran and cooled to 0 ° C under an argon layer. Triethylamine (142 mg, 1.4 mmol) was used, followed by 2,2,2-trifluoroethylamine (139 mg, 1.4 mmol). The reaction was then allowed to warm to room temperature and stirred overnight. Borrowed by adding saturated carbonic acid, the paper size applies Chinese National Standard (CNS) A4 specifications (21 × 297 mm) -78-486469 A7 B7 V. Description of the invention (76) The sodium bicarbonate order should be suspended and ethyl acetate (3x20 Ml) extraction. The crude product was purified by elution on a Merck EM silica gel column with 10% ethyl acetate / hexane to obtain 230 mg (38%) of the title compound as a pale yellow solid.

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 將第D部化合物（1 84毫克，0 · 4毫莫耳）之二 甲基甲醯胺（3毫升）溶液於氬氣層下攪拌，再將碳酸鉀 (55毫克，0 · 4毫莫耳）加入，繼而將實例1第G部 化合物（9 5毫克，0 · 44毫莫耳）加入，再將所得混 合物於室溫下攪拌過夜。而後將反應以乙酸乙酯稀釋，以 水，鹽水清洗，並於無水硫酸鈉上乾燥。繼而將溶劑蒸發 ，再將粗製餘留物於Merck EM矽膠柱上以5%異丙醇/二 氯甲烷洗提而予以純化，即得2 3 0毫克（9 6%)無色 固狀之標題化合物。 分析· C33H3ON3F502+l · 7H2〇之計算值： C，63.35;H，5.37;N，6.72 ;F，1 5 · 1 8 實測值：C，63.24;H，5.34;N，6.45 ;F，1 5 · 1 4 ° 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） ~ 486469 A7 _B7 五、發明説明（77 ) 熔點厂1 6 8 — 1 7 0 °C。 (請先閲讀背面之注意事項再填寫本頁) 實例4 9 一〔4 一〔4 一（1，3 -二氫基一 1 一 合氧基—2H 一異蚓跺一 2 -基）一1 一哌啶基〕丁基〕一 2，7 -二 氟基一N —（2，2，2 -三氟乙基）一 9H -芴—9 一 甲醯胺_；___(Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed the dimethylformamide (3 ml) of the compound of Part D (1.84 mg, 0.4 mmol) ) The solution was stirred under an argon layer, and potassium carbonate (55 mg, 0.4 mmol) was added. Then, the compound of Part G of Example 1 (95 mg, 0.44 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was then diluted with ethyl acetate, washed with water, brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the crude residue was purified by purification on a Merck EM silica gel column with 5% isopropanol / dichloromethane to obtain 230 mg (9 6%) of the title compound as a colorless solid. . Analysis Calculated values of C33H3ON3F502 + 1 and 7H20: C, 63.35; H, 5.37; N, 6.72; F, 1 5 · 1 8 Found: C, 63.24; H, 5.34; N, 6.45; F, 1 5 · 1 4 ° This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 mm) ~ 486469 A7 _B7 V. Description of the invention (77) Melting point factory 1 6 — 1 7 0 ° C. (Please read the precautions on the back before filling out this page) Example 4 9 One [4 One [4 One (1,3-dihydrol-1 1-oxyl-2H-iso-earthion-2-yl) -1 Monopiperidinyl] butyl] -2,7-difluoro-N- (2,2,2-trifluoroethyl) -9H-fluorene-9-methylamidine_; ___

2毫升二甲基甲醯胺及2毫升甲醇溶液（含3 0毫克，2 ml of dimethylformamide and 2 ml of methanol solution (containing 30 mg,

1 0%鈀/碳）於氫氣層（氣球）下攪拌1 8小時，再令 反應通過0·2毫米尼龍濾器中過濾以移去催化劑，繼而 將溶劑蒸發以得無色油狀之粗製產物。將產物於Merck EM 經濟部中央標準局員工消費合作社印製 得 8 即 ： 6 , 值 . 化算 6 純計’ 以。 之 Ν 予物 ο ; 而合 丨 提化 洗題 烷標 7 5 甲之 ， 氯狀+1Η 二固。 4 ·’ \ 色°co 1 胺無 2F50 丙} 5 3 . 異%1N3 %o I326 5 9 ο Η , 以 ^ 533C 上克 1 C 柱毫·· 膠 1點析 矽 9 熔分 Η 510% palladium / carbon) was stirred under a hydrogen layer (balloon) for 18 hours, and the reaction was filtered through a 0.2 mm nylon filter to remove the catalyst, and then the solvent was evaporated to obtain a crude product as a colorless oil. The product was printed on the Merck EM Ministry of Economics Central Standards Bureau's Consumer Cooperatives to obtain 8: 6, value. Conversion 6 pure count ′. Ν 予 物 ο; and combined 丨 extraction and washing topic alkane label 7 5 of the first, chlorine-like + 1Η second solid. 4 · ’\ color ° co 1 amine without 2F50 propyl} 5 3. Iso% 1N3% o I326 5 9 ο Η, with ^ 533C on a 1 C column mill · · glue 1 point analysis of silicon 9 melting fraction Η 5

IX 值 測 實 Η Ν 8 一張 紙 準 標 家 I釐 公 7 9 2 486469 A7 _ B7 五、發明説明（78 ) ” ；F，1 4 · 9 9 ° (請先閲讀背面之注意事項再填寫本頁) 實例5 (Z) — 9 一〔4 一〔4 一（2，3 —二氫基一 1 一合氧 基一 1 Η -異蚓跺一 2 -基）一 1 一哌啶基〕一 2 -丁嫌 基1—Ν—丙某一9Η—芴一9一甲醯胺，單氯氯酸鹽IX value measurement Η Ν 8 One piece of paper quasi bidder I centimeter 7 9 2 486469 A7 _ B7 V. Description of the invention (78) ”; F, 1 4 · 9 9 ° (Please read the notes on the back before filling in (This page) Example 5 (Z) — 9 1 [4 1 [4 1 (2,3 —dihydrol — 1 —oxyl — 1 Η —isoearthyl — 2 —yl) — 1 —piperidinyl] 1-Butanyl 1-N-propyl 9 某一-芴 -9-methylamine, monochlorochlorate

CI 經濟部中央標準局員工消費合作社印製 於0°C下，於氬下，將丁基鋰（8 · 4毫升’ 2 · 5 莫耳濃度之己烷液，2 1毫莫耳）於1 0分鐘期間逐滴加 至芴羧酸（Aldrich化學公司）（2 · 1 0克’ 1 0毫莫 耳）之四氫呋喃（5 0毫升）溶液中。在加入第一當量丁 基鋰期間，反應變得稠厚’同時伴隨白色沈澱物，而於加 入第二當量後變爲黃色且清澈’將反應於〇°C下攪拌2 0 分鐘，而後將順式一 1，4 一二氯基一 2 —丁烯（1 · 2 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ _ 486469 A7 ____B7_ 五、發明説明（79 ) (請先閱讀背面之注意事項再填寫本頁) 毫升，1毫莫耳）於5分鐘期間逐滴加入。添加期間， 反應之顏色淡化，再於0 °C下攪拌3小時，而後倒至1當 量濃度氫氯酸（5 0毫升）中，並以二氯甲烷（3 X 5 0 毫升）萃取r將結合之有機層以鹽水（3 0毫升）清洗， 而後於硫酸鎂上乾燥。蒸發後可得3·5克含晶狀固體之 黃色油狀物。將粗製餘留物以己烷（2 0毫升）碾磨。再 將上層液潷析，繼而將餘留物於高度真空下泵唧，以得 2.93克褐色固狀物。 於室溫下，於氬下，將草醯氯（3 · 6毫升，2 . 0 莫耳濃度之二氯甲烷液，7 · 1 6毫莫耳）加至以上所製 經濟部中央標準局員工消費合作社印製 粗製酸（1 ·42克，4 · 77毫莫耳）及N，N —二甲 基甲醯胺（5滴）之二氯甲烷（1 5毫升）懸浮液中。令 反應起泡10分鐘，而後將反應於室溫下攪拌1.5小時 ，此時所有固體均溶解。將反應於真空中濃縮以得橘色油 狀物，令粗製醯基氯溶於二氯甲烷（1 5毫升）中，再冷 卻至0°C，繼而將丙胺（1 .2毫升，14 · 3毫莫耳） 於1分鐘期間逐滴加入，再將反應於0°C下攪拌1 0分鐘 。令反應分界於乙酸乙酯（5 0毫升）及水（2 0毫升） 間。而後將有機層以1當量濃度氫氯酸（2 X 2 0毫升） 及鹽水（2 0毫升）清洗，及於硫酸鎂上乾燥。蒸發後可 得1 . 7克橘色油狀物，再將之藉於矽膠上（150克） 進行急驟色層分離並以二氯甲烷洗提而予以純化，即得淡 黃色油狀之標題化合物（1 · 38克，84%)。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -82 - 486469 A7 _B7_ 五、發明説明（80 ) B . 9 一〔4 —〔4 一（2，3 —二氫基一 1—合氧基 一 1 Η -異p引晚一 2 -基）一 1 一呢陡基〕一 2 - 丁燦基 1 一 N —丙基一 9H —芴一9 一甲醯胺，單氤氡酸鹽 __ 於氬下，將第A部化合物（440毫克，1 . 30毫 莫耳）及實例1第G部化合物（3 37毫克，1 · 56毫 莫耳）之二甲基甲醯胺（3毫升）混合液於5 0°C下加熱 過夜，冷卻至室溫，而後將溶劑於高度真空下，於室溫下 蒸餾出。令餘留物分界於二氯甲烷（2 0毫升）及飽和碳 酸氫鈉（7毫升）間。再將有機層以鹽水（5毫升）清洗 及於硫酸鈉上乾燥。蒸發後可得9 0 0毫克淡黃色油狀物 ，再將之藉於矽膠（7 5克）上進行急驟色層分離並以3 %甲醇/二氯甲烷洗提而予以純化，以得4 6 7毫克白色 泡沬狀之游離鹼。 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 令以上所製游離胺溶於甲醇（3毫升）中，以1當量 濃度氫氯酸/乙醚（3毫升）處理，而後於真空中濃縮^ 再將所得泡沬狀物於5 0°C下，於高度真空下加熱過夜， 而後於6 0 °C下加熱另6小時，即得白色泡沬固狀之標題 化合物（420毫克，58%)。 分析· C34H38C5N3〇2· 〇 . 7H20之計算值： <：，71·81;Η，6·98;Ν，7·39 ;C 又，6 · 2 3 實測值：C，7 1 · 8 6 ; Η，7 · 3 4 ; Ν，7 · 3 4 ;C 艾，6 · 1 6 〇 遵循實例1至5之步驟，即可另製得下列之化合物。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公董) ' ~~ 一 83 - 486469 A7 _B7__五、發明説明（81 ) 6 · 2，3 —二氫基一 2 —〔1一〔2 —合氧基一 2 — (9 —丙基一 9 Η -荀一 9 一基）乙基〕一 4 一哌: 啶基〕一 1Η —異蚓跺一 1 一酮，單氫氯酸鹽Printed at 0 ° C, under the argon, the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, CI, butyl lithium (8 · 4 ml '2 · 5 Molar hexane solution, 2 1 mmol) Add dropwise over a period of 0 minutes to a solution of ammonium carboxylic acid (Aldrich Chemical Co., Ltd.) (2.10 g '10 mmol) in tetrahydrofuran (50 ml). During the addition of the first equivalent of butyllithium, the reaction became thick 'with a white precipitate, and turned yellow and clear after the addition of the second equivalent.' The reaction was stirred at 0 ° C for 20 minutes, and then the Formula 1, 1, 4-dichloro- 2 -butene (1 · 2 The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 486469 A7 ____B7_ V. Description of the invention (79) (please first Read the notes on the back and fill out this page) (ml, 1 mmol) and add dropwise over 5 minutes. During the addition, the reaction color faded, stirred at 0 ° C for 3 hours, and then poured into 1 equivalent concentration of hydrochloric acid (50 ml), and extracted with dichloromethane (3 x 50 ml). The organic layer was washed with brine (30 ml) and then dried over magnesium sulfate. After evaporation, 3.5 g of a yellow oil containing a crystalline solid was obtained. The crude residue was triturated with hexane (20 ml). The upper layer was decanted, and the residue was pumped under a high vacuum to obtain 2.93 g of a brown solid. At room temperature, under argon, add chlorchloride (3.6 ml, dichloromethane solution with a concentration of 2.0 moles, 7.16 mmol) to the staff of the Central Standards Bureau of the Ministry of Economic Affairs made above. The Consumer Cooperative printed a suspension of crude acid (1.42 g, 4.77 mmol) and N, N-dimethylformamide (5 drops) in dichloromethane (15 ml). The reaction was allowed to foam for 10 minutes, and then the reaction was stirred at room temperature for 1.5 hours, at which time all solids were dissolved. The reaction was concentrated in vacuo to give an orange oil. The crude fluorenyl chloride was dissolved in dichloromethane (15 ml), cooled to 0 ° C, and then propylamine (1.2 ml, 14 · 3 Millimolar) was added dropwise over a period of 1 minute, and the reaction was stirred at 0 ° C for 10 minutes. The reaction was delimited between ethyl acetate (50 ml) and water (20 ml). The organic layer was then washed with 1 equivalent of hydrochloric acid (2 × 20 ml) and brine (20 ml), and dried over magnesium sulfate. After evaporation, 1.7 g of orange oil was obtained, which was then purified by flash chromatography on silica gel (150 g) and purified by dichloromethane to obtain the title compound as a pale yellow oil. (1.38 g, 84%). This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -82-486469 A7 _B7_ V. Description of the invention (80) B. 9 1 [4 — [4 1 (2, 3 — dihydro radical 1 1) —Hydroxy-1, pyrene-isopyridyl, 2-, 2-yl), 1, 1-butanyl], 2-, butanyl, 1-N, propyl, 9H, fluorene, 9, methylamine, monophosphonate __ Dimethylformamide (3 mg, 1.37 mmol) of Part A compound (440 mg, 1.30 mmol) and Example G (3 37 mg, 1.56 mmol) under argon Ml) The mixture was heated at 50 ° C overnight, cooled to room temperature, and then the solvent was distilled under high vacuum at room temperature. The residue was delimited between dichloromethane (20 ml) and saturated sodium bicarbonate (7 ml). The organic layer was washed with brine (5 ml) and dried over sodium sulfate. After evaporation, 900 mg of a pale yellow oil was obtained, which was then purified by flash chromatography on silica gel (75 g) and purified by extraction with 3% methanol / dichloromethane to give 4 6 7 mg of white foamy free base. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Make the free amine prepared above dissolved in methanol (3 ml), and use 1 equivalent concentration of hydrochloric acid / ether (3 ml ) Treatment, and then concentrated in vacuo ^ and then the resulting foamed object was heated at 50 ° C under high vacuum overnight, and then heated at 60 ° C for another 6 hours, to obtain a white foamed solid Title compound (420 mg, 58%). Analysis · C34H38C5N3〇2. Calculated value of 7H20: <:, 71 · 81; Η, 6.98; N, 7.39; C, 6, 2 3 Measured value: C, 7 1 · 8 6 Η, 7 · 3 4; N, 7 · 3 4; C AI, 6. · 16 〇 The following compounds can be prepared by following the steps of Examples 1 to 5. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 public directors) '~~ 83-486469 A7 _B7__ V. Description of the invention (81) 6 · 2, 3 —dihydro 1 — 2 — [1 一 [ 2 —Hydroxy-2- (9-propyl-9 fluorene-fluorene-9-yl) ethyl] -4 piperyl: pyridinyl] -1 1 fluorene-isoearmidine-1 1 ketone, monohydrochloride

經濟部中央標隼局員工消費合作社印製 MS (ES) 465 (Μ + Η) 熔點·146 - 149°C 分析· C3iH33Cj?N202· 〇 · 95H20 之計算： 計算值：C，71.85;H，6.79;N，5.41 實測值：C，7 2 · 2 9 ; Η，6 · 2 2 ; N，5 . 3 7 〇 7· (£)—9一〔4一〔4一（2，3—二氫基一1 一合氧基一 1 Η -異蚓跺一 2 -基）一 1 一哌啶基 〕一 2 —丁烯基〕一Ν—丙基一 9Η —芴一 9 一甲 醯胺，單氫氯酸鹽Printed MS (ES) 465 (Μ + Η) by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs Melting point · 146-149 ° C Analysis · C3iH33Cj? N202 · 〇 · 95H20 Calculation: Calculated value: C, 71.85; H, 6.79 ; N, 5.41 found: C, 7 2 · 2 9; Η, 6 · 2 2; N, 5. 3 7 〇 ·· (£) —9 a [4 a [4 a (2, 3-dihydro 1-1-oxyl-1 -iso-earthmidine-2 -yl)-1-piperidinyl]-2-butenyl]-N-propyl-9--9-methylamine, mono Hydrochloride

本紙張尺度適用中國國家標準（CNS )八4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（82 ) Μ S ( C ) 5 2 0( Μ + Η ) 熔 點 • 1 1 5 — 1 16 • 5 °C 分 析 • C 3 4 Η 3 T Ν 3 〇 2 之 計 算： 計 算 值 ; C f 7 8 • 5 8 ; Η， 7 · 1 8 ；Ν， ，8 、 .0 實 測 值 : C 7 8 • 4 9 ； Η ， 7 . 2 6 ；Ν ， ，8 . .0 8 · 9 —〔3—〔4 一（2，3-二氫基—1—合氧基 一 1 Η —異D引晦一 2 —基）一 1 一呢淀基〕丙基〕 一 N —丙基一 9 Η —苟一 9 一甲酸胺The size of this paper applies to China National Standard (CNS) 8 4 specifications (210X297 mm) (Please read the precautions on the back before filling out this page) 486469 A7 B7 V. Description of the invention (82) MS (C) 5 2 0 ( Μ + Η) Melting point • 1 15 — 1 16 • 5 ° C Analysis • Calculation of C 3 4 Η 3 T Ν 3 〇2: Calculated value; C f 7 8 • 5 8; Η, 7 · 1 8; Ν ,, 8, .0 Found: C 7 8 • 4 9; Η, 7. 2 6; Ν,, 8. .0 8 · 9 — [3— [4 1 (2,3-dihydro-1 —Hydroxy-1 hydrazone —Isodium amine —2 —yl) — 1 monomorpho] propyl] —N —propyl —9 hydrazine — 9-9 monocarboxylic acid amine

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 M , S . (ES，+ 離子）m/e 5 0 8 ( Μ + Η ) 熔點.1 7 2 — 1 7 5 °C計算值：C，78.07;H，7.34;Ν，8·28 實測值：C，77.80;H，7.50;N，8.10 ο 實例9 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -85 - 486469 A7 B7(Please read the notes on the back before filling out this page) Printed by M, S. (ES, + ion) m / e 5 0 8 (Μ + Η) Melting point printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Melting point. 1 7 2 — 1 7 5 ° C Calculated value: C, 78.07; H, 7.34; N, 8.28 Measured value: C, 77.80; H, 7.50; N, 8.10 ο Example 9 This paper standard applies to China National Standard (CNS) Α4 (210X297 mm) -85-486469 A7 B7

A.A.

(請先閱讀背面之注意事項再填寫本頁) 標題化合物係購自Aldrich化學公司。 B.(Please read the notes on the back before filling out this page) The title compound was purchased from Aldrich Chemical Company. B.

經濟部中央標準局員工消費合作社印製 將第A部醇（1 · 5 8克，10 · 〇毫莫耳）及丁烷 硫赶（0 · 72克’ 8 · 00毫莫耳）之10毫升二氯甲 烷溶液於一 2 0 °C下以三氟化硼醚酸酯（1 · 28克， 9 . 00毫莫耳）處理。再將反應於一 2 0 °C下攪拌1小 時，而後加溫至室溫。攪拌1 8小時後，將反應於真空中 濃縮，再將粗製產物藉於矽膠（1 0 0克）上進行柱色層 分離並以己烷及1 : 9二氯甲烷/己烷先後洗提而予以純 化，即得1 · 54克（75%)無色油狀之標題化合物。 ^紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ~ 486469 A7 B7 五、發明説明（84 C.Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 10 ml of Part A alcohol (1.58 g, 10.0 mmol) and butanesulfide (0.72 g '8. 00 mmol) The dichloromethane solution was treated with boron trifluoride etherate (1.28 g, 9.0 mmol) at -20 ° C. The reaction was stirred at 20 ° C for 1 hour, and then warmed to room temperature. After stirring for 18 hours, the reaction was concentrated in vacuo, and the crude product was separated by column chromatography on silica gel (100 g) and eluted with hexane followed by 1: 9 dichloromethane / hexane. Purification gave 1.54 g (75%) of the title compound as a colorless oil. ^ Paper size applies to China National Standard (CNS) A4 (210X297 mm) ~ 486469 A7 B7 V. Description of the invention (84 C.

於一 7 8 °C下，將第 3·93毫莫耳）之10 之己烷液（1 · 75毫升 一氯基一4一溴基一丁烷 )處 小時 乙酸 。而 並先 理。而後將 。而後將反 乙酯稀釋。 後將粗製產 以 2 : 9 8 :8 5 二氯 0 0 克（7 反應攪拌 應以3 0 再將有機 物藉於矽 丙酮/二 甲烷/己 3 % )無 B部化合物（1 · 〇克， 毫升四氫呋喃溶液先以正丁基鋰 ，4.40毫莫耳），繼而以1 (0·81克，4·70毫莫耳 0 . 5小時，再加溫至室溫1 8 毫升水性氯化銨溶液及3 0毫升 部分予以乾燥（硫酸鈉）及濃縮 膠（50克）上進行柱色層分離 氯甲烷（5 0 0毫升），後以 烷洗提而予以純化，即得 色狀之標題化合物。 (請先閲讀背面之注意事項再填寫本頁) D. 經濟部中夬標準局員工消費合作社印製At 7.8 ° C, place 3.93 millimoles of 10 hexanes (1.75 ml of monochloro-4, bromomonobutane) in acetic acid for 1 hour. And do it first. Then will. The trans-ethyl ester was then diluted. Then, the crude product was 2: 9 8: 8 5 0 0 g of dichloride (7 should be stirred at 30 for the reaction, and then the organic matter should be borrowed from silicon acetone / dimethane / hexane 3%) without Part B compound (1.0 g, The tetrahydrofuran solution was firstly n-butyllithium, 4.40 millimoles, then 1 (0.81 g, 4.70 millimoles for 0.5 hours, and then warmed to room temperature. And 30 ml portion was dried (sodium sulfate) and concentrated gel (50 g) was separated by column chromatography for methyl chloride (500 ml), and then purified by alkane elution to obtain the title compound as a color. (Please read the notes on the back before filling out this page) D. Printed by the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs

於0°C下，將3 —氯基過苯甲酸（0 · 37克，80 重量％= 0 · 1 7 2毫莫耳）一次地加至第C部硫化物（ 0 · 30克，〇 · 86毫莫耳）之二氯甲烷（5毫升）溶 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469 A7 ___B7_五、發明説明（85 ) 液中/再將混合物攪拌1小時，令之分界於0 .1莫耳濃 度碳酸鉀（2 0毫升）及乙醚（3 0毫升）間。繼而將有 機部分予以乾燥（硫酸鈉）及濃縮。再將粗製產物藉於矽 膠（5 0克）上進行柱色層分離並以1 5 : 8 5乙酸乙酯 /己烷洗提而予以純化，以得0 · 2 4克無色油狀之碉。 於室溫下，將碘化鈉（1 . 00克，6 · 66毫莫耳 )一次地加至氯化硕（0 · 24克，0 · 64毫莫耳）之 2 — 丁酮（1 0毫升）溶液中。當以水（2 0毫升）及乙 醚（3 0毫升）稀釋之時，令混合物迴流3 0小時。再將 有機部分予以乾燥（硫酸鈉）及濃縮。繼而將粗製產物藉 於矽膠（5 0克）上進行柱色層分離並以1 5 :8 5乙酸 乙酯/己烷洗提而予以純化，即得0 · 24克（81%) 無色油狀之標題化合物。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製At 0 ° C, 3-chloroperbenzoic acid (0. 37 g, 80% by weight = 0. 172 mmol) was added to the sulfide in Part C (0. 30 g, 0. 86 millimoles) of dichloromethane (5 ml). The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 486469 A7 ___B7_ V. Description of the invention (85) in liquid / stir the mixture 1 Hour, make the boundary between 0.1 Molar potassium carbonate (20 ml) and ether (30 ml). The organic portion was then dried (sodium sulfate) and concentrated. The crude product was separated by column chromatography on silica gel (50 g) and purified by elution with 15:85 ethyl acetate / hexane to obtain 0.24 g of tincture as a colorless oil. At room temperature, sodium iodide (1,000 g, 6.66 mmol) was added all at once to 2-butanone (1.00 g, 0.42 g, 0.64 mmol) Ml) solution. When diluted with water (20 ml) and ether (30 ml), the mixture was refluxed for 30 hours. The organic portion was dried (sodium sulfate) and concentrated. Then, the crude product was purified by column chromatography on silica gel (50 g) and eluted with 15: 8 5 ethyl acetate / hexane to obtain 0.24 g (81%) of a colorless oil. Title compound. (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Ε· IΕ · I

於室溫下，將0 · 38克（1 · 80毫莫耳） 〇At room temperature, 0.38 g (1.80 mmol) will be applied.

NH (依實例1第G部所述之方法製得） 本紙張尺度適用中國國家標準（CNS) A4規格（210x297公釐）一 88 _ 486469 經濟部中央標準局員工消費合作社印製 A7 _ B7五、發明説明（86 ) 加至已备拌之0 · 70克（1 · 49毫莫耳）第D部化合 物之6毫升二甲基甲醯胺溶液中，再將反應混合物加溫至 5 5 °C，而後令之攪拌2 4小時。繼而將混合物以碳酸氫 鈉溶液（5 0毫升）及乙酸乙酯（5 0毫升）稀釋。再將 諸層分離，並將有機相乾燥（硫酸鈉）及濃縮。而後將餘 留物藉於矽膠（1 0 0克）上進行急驟柱色層分離並以5 :95甲醇/二氯甲烷（700毫升）及5: 95 : 0 · 5甲醇/二氯甲烷/氨（1升）先後洗提而予以純化 。再收集純溶離份並予濃縮，即得0 · 70克（85%) 稠厚油狀之標題化合物，其於靜置後固化。 熔點· 1 2 8 — 1 3 1 °C。 分析· C34H4〇N203S · 0 · 45H20 之計算值： <：，72·29;Η，7·30;Ν，4·96 ;S，5 · 7 6 實測值：C，72.25;H，7.15;N，5.00 ;S，5 · 6 9 〇 實例1 0 〔9 一〔4 一〔4 一〔〔 （1 ，1 一二甲基乙氧基）羰基 〕胺基〕一 1 一哌啶基〕丁基〕一 N -丙基一 9H -芴一 9 一甲醯胳__ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469 A7 B7 五、發明説明（87 ) μNH (produced according to the method described in Part G of Example 1) This paper size applies the Chinese National Standard (CNS) A4 size (210x297 mm)-88 _ 486469 Printed by A7 _ B7 of the Central Consumers Bureau of the Ministry of Economic Affairs 2. Description of the invention (86) Add to a solution of 0. 70 g (1.49 mmol) of the D compound in 6 ml of dimethylformamide solution, and warm the reaction mixture to 5 5 ° C, and then allowed to stir for 24 hours. The mixture was then diluted with sodium bicarbonate solution (50 ml) and ethyl acetate (50 ml). The layers were separated and the organic phase was dried (sodium sulfate) and concentrated. The residue was then subjected to flash column chromatography on silica gel (100 g) and separated with 5:95 methanol / dichloromethane (700 ml) and 5: 95: 0 · 5 methanol / dichloromethane / ammonia. (1 liter) was eluted and purified. The pure soluble fractions were collected and concentrated to give 0.70 g (85%) of the title compound as a thick oil, which solidified upon standing. Melting point · 1 2 8 — 1 3 1 ° C. Analysis · Calculated value of C34H4〇N203S · 0 · 45H20: <:, 72 · 29; Η, 7.30; N, 4.96; S, 5 · 7 6 Found: C, 72.25; H, 7.15; N, 5.00; S, 5.6 9 〇 Example 10 [9 1 [4 1 [4 1 [[(1,1 -dimethylethoxy) carbonyl] amino]-1 -piperidinyl] butyl 〕] -N-propyl-9H-芴 -9 9 甲 __ (Please read the notes on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 486469 A7 B7 V. Description of the invention (87) μ

經濟部中央標準局員工消費合作社印製 A · 〔1 一（苯甲基）一 4 一哌啶基〕胺基甲酸，1， 1 一二甲某乙醋___ 於0乇下，將二碳酸二特丁酯（2 5 · 2克，1 1 6 毫莫耳）之二氯甲烷（5 0毫升）溶液逐滴加至4 一胺基 一1 一笮基哌啶（20 · 0克，105毫莫耳）之二氯甲 烷（1 5 0毫升）溶液中。加完後，將反應加溫至室溫。 而後令反應保持於此溫下2小時。繼而將反應蒸發至乾。 再將所得餘留物由乙醚中予以再結晶，即得白色固狀（熔 點 1 19 一 121 °C)之化合物 A (23 · 5 克，76% )° B . 4 一哌啶基胺某甲酸，1 ，1 一二甲基乙酯 將64 · 94克（〇 · 224莫耳）化合物A及 25 · 6毫升（0 · 447莫耳）乙酸之500毫升無水 乙醇懸浮液加溫以令所有固體溶解。冷卻後，將6·5克 (1重量％) 10%鈀/碳加入，再將混合物於帕爾儀器 上’於40ps i之初始氫壓下搖動23小時。繼而將催 化劑藉過濾法移除，再將溶液濃縮成清澈油狀物，並令之 本紙張纽適财關家標準（（：叫44規格丨210、;< 297公釐) 一 -90 - (請先閲讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（88 ) 溶於1' 5升氯仿中》而後將有機相以己以氯化鈉飽和之 3當量濃度氫氧化鉀溶液（2 X 7 5毫升）清洗。再將水 性層以氯仿（5 X 2 0 0毫升）反萃取。繼而將結合之有 機相乾燥（硫酸鈉）及濃縮以得6 5克白色固狀物，令之 再溶於1 . 5升氯仿中，再以鹽水（2 x 200毫升）清 洗以移去餘留之乙酸鹽。而後將結合之水性層反萃取，再 將結合之有機相乾燥（硫酸鈉）及濃縮，即得40 . 15 克（90%)白色固狀之化合物B (熔點156 — 159 °C )。c.Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. [1 (benzyl) -4 piperidinyl] amino formic acid, 1, 1 and 2 methyl ethyl vinegar. A solution of ditert-butyl ester (2.5 g, 1 16 mmol) in dichloromethane (50 ml) was added dropwise to 4-monoamino-1,1-methylpiperidine (20.0 g, 105 MM) in dichloromethane (150 ml). After the addition was complete, the reaction was warmed to room temperature. The reaction was then kept at this temperature for 2 hours. The reaction was then evaporated to dryness. The obtained residue was recrystallized from diethyl ether to obtain a white solid (melting point 1 19 to 121 ° C) of compound A (23 · 5 g, 76%) ° B. 4 piperidylamine formic acid 1,1,1,2-dimethylethyl ether A warming of 64.94 g (0.224 mol) of compound A and 25.6 ml (0.447 mol) of acetic acid in 500 ml of absolute ethanol was allowed to warm all solids Dissolve. After cooling, 6.5 g (1% by weight) of 10% palladium / carbon was added, and the mixture was shaken on a Parr apparatus' under an initial hydrogen pressure of 40 ps for 23 hours. Then the catalyst was removed by filtration, and then the solution was concentrated to a clear oil, and the paper was made to New Zealand's family standard ((: called 44 specifications 丨 210 ,; < 297 mm) a -90- (Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (88) Dissolved in 1 '5 liters of chloroform "Then the organic phase was saturated with sodium chloride at a concentration of 3 equivalents of potassium hydroxide The solution (2 X 7 5 ml) was washed. The aqueous layer was back-extracted with chloroform (5 X 2000 ml). The combined organic phases were then dried (sodium sulfate) and concentrated to give 65 g of a white solid. It was redissolved in 1.5 liters of chloroform and washed with brine (2 x 200 ml) to remove the remaining acetate. The combined aqueous layer was then back-extracted and the combined organic phase was dried (sodium sulfate ) And concentrated to obtain 40.15 g (90%) of Compound B (melting point 156-159 ° C) as a white solid. C.

0 CHa H 〇-7< CH3CH3 (請先閲讀背面之注意事項再填寫本頁) 經濟部中夬標準局員工消費合作社印製 將實例5第A部化合物（6 · 0克，17 . 6毫莫耳 )及第B部化合物（2 · 88克，16 · 0毫莫耳）之二 甲基甲醯胺（3毫升）溶液於5 0 °C下攪拌過夜。再將乙 酸乙酯（1 5 0毫升）加入，而後將有機層以飽和碳酸儀 鈉溶液（2x30毫升），水（2x50毫升），鹽水（ 2 X 5 0毫升）清洗，再於硫酸鎂上乾燥。而後藉於矽膠 (300克）上進行急驟色層分離，以2·5%甲醇之二 氯甲烷液裝填及洗提而予以純化。繼而結合純溶離份，並 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 91 486469 經濟部中央標準局員工消費合作社印製 A7 ______B7 _五、發明説明（89 ) 予蒸發\即得無色油狀之標題化合物（3 . 0克，3 4 % )0 D· 9—〔4一〔4一〔 〔 （1，1一二甲基乙氧基） 鐵基〕胺基〕一 1 一哌_基〕丁基〕—N -丙基一 9H — 茨一 9 一甲酿胺_ 於室溫下，將鈀/活性碳（1 0 %，3 0 0毫克）加 至第C部化合物（3 · 0克，5 · 89毫莫耳）之甲醇（ 1 0毫升）溶液中。再將反應於室溫下氫化（氣球）1 8 小時。而後將反應過濾，再將濾液蒸發以得白色固狀物。 繼而將所得固狀物由乙酸乙酯/己烷中予以再結晶，即得 白色固狀之標題化合物（2 .90克，.97%)。 熔點· 118 — 120 °C。 分析· C3iH43N303· 2 · 4H20 之計算值： C，67.83;H，8.78;N，7.65 實測值：C，67.45;H，8.33;N，7.52 〇 實例1 1 N -〔2 -〔4 一（1，3 -二氫基一 1 一合氧基一 2H 一異蚓跺一 2 -基）-1 一哌啶基〕乙基〕一 9 一丙基一 9H —芴一 9 -甲醯胺_ 一_ (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -92 - 486469 A7 B7 五、發明説明（900 CHa H 〇-7 < CH3CH3 (Please read the notes on the back before filling this page) Printed by the Consumers' Cooperative of the China Standards Bureau, Ministry of Economic Affairs, Example 5 Part A Compound (6.0 g, 17.6 mmol) Ear) and Part B compound (2.88 g, 16.0 mmol) in dimethylformamide (3 ml) was stirred at 50 ° C overnight. Ethyl acetate (150 ml) was added, and the organic layer was washed with saturated sodium carbonate solution (2 x 30 ml), water (2 x 50 ml), brine (2 x 50 ml), and dried over magnesium sulfate. . It was then purified by flash chromatography on silica gel (300 g), and then filled with 2.5% methanol in dichloromethane. Then combined with pure soluble fractions, and this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 91 486469 Printed by A7 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. The title compound was obtained as a colorless oil (3.0 g, 34%). 0 D · 9— [4-a [4-a [[(1,1-dimethylethoxy) iron] amine] -1] 1-piperidinyl] butyl] -N-propyl-9H—z-9-9 methylamine_ At room temperature, add palladium / activated carbon (10%, 300 mg) to the compound in Part C (3.0 g, 5.89 mmol) in methanol (10 ml). The reaction was further hydrogenated (balloon) at room temperature for 18 hours. The reaction was then filtered and the filtrate was evaporated to give a white solid. The solid was recrystallized from ethyl acetate / hexane to give the title compound (2.90 g, .97%) as a white solid. Melting point · 118 — 120 ° C. Analysis · Calculated values of C3iH43N303 · 2 · 4H20: C, 67.83; H, 8.78; N, 7.65 Found: C, 67.45; H, 8.33; N, 7.52 ○ Example 1 1 N-[2-[4 1 (1 , 3 -dihydro-1, 1-oxyl-2H, 1-isopropanthyl-2-yl) -1, 1-piperidinyl] ethyl] -9, 9-propyl-1 9H —fluorene 9-formamidine_ 1 _ (Please read the notes on the back before filling out this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -92-486469 A7 B7 V. Description of the invention (90

(請先閲讀背面之注意事項再填寫本頁) 於氮下，將1，1 * 一羰基二咪唑（1 . 3 5克， 經濟部t央標準局員工消費合作社印製 8 · 32毫莫耳）加至實例2第B (1)部化合物（2克 ，7 · 93毫莫耳）之二氯甲烷（3 0毫升）溶液中。1 小時後，將乙醇胺（〇 · 486克，7 · 95毫莫耳）加 入’繼而將二甲基甲醯胺（1 · 5毫升）加入以促進胺之 溶解，而後令反應於室溫下攪拌過夜。2 4小時後，將反 應混合物以飽和碳酸氫鈉稀釋，再將水性層以二氯甲烷萃 取兩次。而後將結.合之有機相以水清洗，於硫酸鈉上乾燥 及於真空中蒸發以得油狀餘留物（2 · 5 5克）。再將餘 留物藉急驟柱色層分離法（二氧化矽，3 5 0毫升）以 3 0 %乙酸乙酯：二氯甲烷洗提而予以純化，即得無色固 狀之標題化合物（1 · 73克，74%產率）^ 本紙張又度適用中國國家標準（CNS)A4規格（210X297公釐）_ 486469 Α7 Β7 五、發明説明（91 )(Please read the notes on the back before filling out this page) Under nitrogen, print 1, · 1 * monocarbonyldiimidazole (1.35 g, 8.25 millimolars from the Consumers Cooperative of the Central Standards Bureau, Ministry of Economic Affairs). ) Was added to a dichloromethane (30 ml) solution of the compound of Part B (1) (2 g, 7.93 mmol) in Example 2. After 1 hour, ethanolamine (0.486 g, 7.95 mmol) was added, followed by dimethylformamide (1.5 ml) to promote dissolution of the amine, and the reaction was allowed to stir at room temperature. overnight. After 24 hours, the reaction mixture was diluted with saturated sodium bicarbonate, and the aqueous layer was extracted twice with dichloromethane. The combined organic phase was then washed with water, dried over sodium sulfate and evaporated in vacuo to obtain an oily residue (2.55 g). The residue was purified by flash column chromatography (silica dioxide, 350 ml) with 30% ethyl acetate: dichloromethane to obtain the title compound (1 · 73 grams, 74% yield) ^ This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 486469 Α7 Β7 V. Description of the invention (91)

BB

於5.3 ，5 . 4 · 7 反應攪 倒至1 萃取4 空中蒸 物藉急 ，以4 狀之標 0 〇C 下， 0毫莫耳 2 2毫莫 4毫莫耳 拌2小時 0 %水性 次，再將 發以得油 驟柱色層 :1二氯 題化合物 於氫下， )及N -耳）加至 )之二氯 β而後將 亞硫酸氫 結合之有 狀棕色餘 分離法（ 甲烷：己 (1.5 將三苯膦（1 溴基琥珀醯亞 第Α部化合物 甲烷（3 0毫 反應混合物以 鈉中。繼而將 機相於硫酸鈉 留物（3 · 4 二氧化矽，5 烷洗提而予以 2 克，8 9 . .3 9 胺（0 (1 · 升）溶 二氯甲 水性層 上乾燥 克）。 X 1 8 純化， 5 %產 克* • 9 3 0 克 4克， 液中*再令 烷稀釋，再 以二氯甲烷 ，而後於真 繼而將餘留 .5公分） 即得無色掘 率）0 經濟部中夬標準局貝工消費合作社印製 C . N —〔2 -〔4— (1，3 —二氫基一1 一 合氧基 —2 H —異巧|卩朵一 2 -基）一 1 一呢淀基〕乙基〕一 9 丙基一 9 H —芴一 9 一甲醯胺 _____ 將第B部化合物（ 5 20毫克，1 · 45毫莫耳）及 實例1第G部化合物（3 1 5毫克，1 · 45毫莫耳）之 二甲基甲醯胺（1 . 5毫升）溶液於氬下攪拌1小時’ @ 而將碳酸鉀（200毫克，1 . 45毫莫耳）及二甲 (請先閲讀背面之注意事項再填寫本頁)At 5.3, 5.4 · 7, the reaction was stirred down to 1 and the extraction was carried out in the air. At 4 ° C, 0 mmol, 2 mmol, 2 mmol, and 4 mmol were mixed for 2 hours and 0% water. Then the color column of the oil column was obtained: 1 dichloro title compound under hydrogen,) and N-ear) were added to the dichloro beta of), and then the hydrogenation combined with hydrogen sulfite was used to form a brown residual separation method (methane: hexane (1.5 Triphenylphosphine (1 bromosuccinate subunit A compound methane (30 mmol reaction mixture in sodium. Then the organic phase was eluted with sodium sulfate (3.4 silica, 5 alkane) Give 2 g, 8 9.. 3 9 amines (0 (1 · liter) dissolved in dichloromethane aqueous layer dry gram). X 1 8 purified, 5% yield * * 9 3 0 g 4 g, in liquid * Dilute the alkane, then dichloromethane, and then leave the remaining .5 cm) to get the colorless excavation rate) 0 Printed by C. N — [2-[4 — (1,3 —dihydro — 1 —oxy — 2 H —octadecyl | 2 — 2 —yl) — 1 —Nanthyl] ethyl] — 9 propyl — 9 H — fluorene — 9 Methylamine _____ will A solution of the compound in Part B (5.20 mg, 1.55 mmol) and the compound in Part G of Example 1 (3.15 mg, 1.55 mmol) in dimethylformamide (1.5 ml) Stir for 1 hour under argon '@ while adding potassium carbonate (200 mg, 1.45 mmol) and Dimethyl (Please read the precautions on the back before filling this page)

本紙張尺度適用中國國家標準（CNS) Α4規格（210Χ 297公釐） 486469 Α7 Β7 五、發明説明（92 ) 醯胺（、〇 · 5毫升）加入。2 4小時後，令反應分界於飽 和碳酸氫鈉及乙酸乙酯間。再將水性層以乙酸乙酯，氯仿 萃取，及以二氯甲烷萃取兩次。而後將結合之有機相於硫 酸鈉上乾燥，再於真空中移去揮發物以得油狀-固狀餘留 物（7 2 0毫克）。繼而將餘留物藉急驟柱色層分離法（ 二氧化矽，5x8公分），以1%甲醇：二氯甲烷而後5 %甲醇：二氯甲烷洗提而予以純化，即得無色固狀之標題 化合物（184毫克，25%產率）。熔點219-2 2 1 0C 〇 分析· C32H35N3〇2· 0 · 3 2H2〇之計算值： C，76.97;H，7.19;N，8.42 實測值：C ’ 76 · 88 ; Η，7 · 16 ; N，8 · 51 賨例1 2 .9 一〔4 一〔4 一〔 〔2 -（苯氧基苯基）羰基〕胺基〕 一 1 一哌啶基〕丁基〕一 Ν —丙基一 9Η -芴一 9 一甲醯 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) Μ_ 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 486469 A7 B7 五、發明説明（93 )This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 486469 A7 B7 V. Description of the invention (92) Add amidine (0.5ml). After 24 hours, the reaction was delimited between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate, chloroform, and twice with dichloromethane. The combined organic phases were then dried over sodium sulfate and the volatiles were removed in vacuo to give an oily-solid residue (720 mg). The residue was then purified by flash column chromatography (silica dioxide, 5x8 cm) with 1% methanol: dichloromethane and then 5% methanol: dichloromethane to obtain the title, a colorless solid. Compound (184 mg, 25% yield). Melting point 219-2 2 1 0C 〇 Analysis · Calculated value of C32H35N3 〇 2 · 3 2H2 〇: C, 76.97; H, 7.19; N, 8.42 Found: C '76 · 88; Η, 7 · 16; N , 8 · 51 賨 Example 1 2 .9-[4-[4-[[2- (phenoxyphenyl) carbonyl] amino]-1 -piperidinyl] butyl] -N -propyl -9Η -芴 19 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Μ_ This paper size applies to China National Standard (CNS) Α4 size (210X 297 mm) 486469 A7 B7 V. Description of Invention (93)

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-----------I (請先聞讀背面之注意事項再填寫本頁)----------- I (Please read the notes on the back before filling in this page)

、1T 於室溫下，將氫氯酸之二噁烷溶液（4當量濃度， 1 0毫升，4 0毫莫耳）加至實例1 0第A部化合物（ 2 · 65克，5 · 20毫莫耳）之二噁烷（10毫升）溶 液中。再將反應於.室溫下攪拌3 · 5小時。.繼而將反應蒸 發以得白色固狀物。而後將所得固狀物由甲醇/水中予以 再結晶，即得白色固狀之標題化合物（.2 . 4克，9 7% )° 熔點· 1 5 6 - 1 6 0 °C。 分析· C2eH37Ci22N30 · 1 · 11120之計算值： C，6 2.67;H，7.93;N，8.43 實測值：C，62.63;H，7.87;N，8.46 〇 本紙張尺度適用中國國家標準（CNS ) Μ規格（210X297公釐丁 Γ7 一~" 線 經濟部中央標準局員工消費合作社印製 486469 經濟部中央標準局員工消費合作社印製 A7 __B7 五、發明説明（94 ) B · 9 -〔4 一〔4 一〔〔2 —（苯氧基苯基）羰基〕胺 基〕一 1 一哌啶基〕丁基〕—N -丙基一 9H -芴一 9 一 甲醯胺 __—_ _ 於室溫下，將草醯氯之二氯甲烷溶液（2 · 0莫耳濃 度，1 · 28毫升，2 · 56毫莫耳）逐滴加至2 -苯氧 基苯甲酸（購自Aldrich) (500毫克，2 .33毫莫 耳）及二甲基甲醯胺（1滴）之二氯甲烷（1 0毫升）溶 液中。加完後，逸出之氣體乃持續起泡10分鐘。將反應 於室溫下攪拌6 0分鐘，而後於真空中濃縮以得粗製油狀 物。於0°C下，於氬下，將第A部化合物（1 · 12克， 2 . 33毫莫耳）之二氯甲烷（2毫升）溶液逐滴加至粗 製醯基氯及三乙胺（1 ·14毫升，8 · 16毫莫耳）之 二氯甲烷（1 0毫升）溶液中。再將反應於0°C下攪拌 3 0分鐘。而後將乙酸乙酯（1 〇 〇毫升）加入以將反應 稀釋，再將所得溶液以水（2 X 3 0毫升），鹽水（2 X 3 0毫升）清洗，並於硫酸鎂上乾燥。蒸發後可得粗製膠 狀物β將其藉於矽膠（1 0 0克）上進行急驟色層分離， 以2.5%甲醇之二氯甲烷液裝填及洗提而予以純化。而 後結合純溶離份，再予蒸發以得無色膠狀物β繼而將所得 產物以乙醚碾磨，即得白色固狀之標題化合物（7 2 0毫 克，5 1 % )。 熔點· 149 一 152 °C。 分析· C39H43N3〇3· 0 · 2H2〇之計算值： 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 486469 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（95 ) ~ C，7 7 · 3 8 ; Η，7 · 2 3 ; N，6 · 9 4 實測值：C，77.37;H，7.39;N，6.89 〇 眚例1 3至2 0 遵循實例1至1 2所示之步驟，即製得下列化合物。, 1T At room temperature, add a solution of hydrochloric acid in dioxane (4 equivalents, 10 ml, 40 mmol) to the compound in Part 10 of Example 10 (2.665 g, 5.20 mmol) Mol) in dioxane (10 ml). The reaction was stirred at room temperature for 3.5 hours. The reaction was then evaporated to give a white solid. The solid obtained was then recrystallized from methanol / water to obtain the title compound (.2.4 g, 9 7%) as a white solid. Melting point · 156-160 ° C. Analysis · Calculated values of C2eH37Ci22N30 · 1 · 11120: C, 6 2.67; H, 7.93; N, 8.43 Measured values: C, 62.63; H, 7.87; N, 8.46 〇 This paper size applies the Chinese National Standard (CNS) M specifications (210X297 mm Ding Γ7 I ~ " Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed 486469 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics A7 __B7 V. Description of the invention (94) Mono [[2- (phenoxyphenyl) carbonyl] amino] -1 monopiperidinyl] butyl] -N-propyl-9H-fluorene-9 monomethylamine _____ at room temperature Next, dichloromethane solution of chloramphenicol (2.0 mole concentration, 1.28 ml, 2.56 mmol) was added dropwise to 2-phenoxybenzoic acid (purchased from Aldrich) (500 mg , 2.33 mmol) and dimethylformamide (1 drop) in dichloromethane (10 ml). After the addition is complete, the escaping gas continues to bubble for 10 minutes. The reaction will be in the chamber Stir for 60 minutes at room temperature, then concentrate in vacuo to give a crude oil. At 0 ° C, under argon, remove Part A compound (1.12 g, 2.33 mmol) Ear) of dichloromethane (2 ml) was added dropwise to a solution of crude fluorenyl chloride and triethylamine (1.14 ml, 8.16 mmol) in dichloromethane (10 ml). The reaction was stirred at 0 ° C for 30 minutes. Then ethyl acetate (100 ml) was added to dilute the reaction, and the resulting solution was water (2 X 30 ml), brine (2 X 30 ml) It was washed and dried over magnesium sulfate. After evaporation, a crude gum β was obtained, which was separated on silica gel (100 g) for rapid color layer separation, and filled with 2.5% methanol in dichloromethane and eluted. It was purified. The pure fractions were combined and evaporated to give a colorless gum β. The product was then triturated with ether to give the title compound (720 mg, 51%) as a white solid. Melting point · 149 152 ° C. Analysis · Calculated value of C39H43N3〇3 · 0 · 2H2〇: This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) 486469 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description ( 95) ~ C, 7 7 · 3 8; Η, 7 · 2 3; N, 6 · 9 4 Found: C, 77.37; H, 7.39; N, 6.89 ○ Example 1 3 to 2 0 Follow Examples 1 to In the step shown in Fig. 12, the following compounds were prepared.

9 一〔5 —〔4一〔1 ，3 —二氫基一 1 一合氧基一 2 Η 一異蚓跺一 2 -基）一 1 一哌啶基〕戊基〕一 Ν -丙基一 —芴一9一甲醯胺 熔點，146 — 1.48 °C MS(ES，+離子）：536(M+H) 分析· C35H42C I Ν302· 1 · 8H20 之計算值： C，6 9.76;H，7.29;N，6.97 ;C I，5 · 8 8 實測值：C，6 9 . 7 Ο ; Η，7 · 3 9 ; N，7 · Ο Ο ;C I ，5 . 7 4 β 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) -·" -98 - 486469 A7 B7 五、發明説明（96 )9- [5 — [4— [1,3-dihydrol — 1 —oxy] 2 — isofluorene — 2 —yl) — 1 — piperidinyl] pentyl] — N-propyl— — 芴 -9-Methylformamide melting point, 146 — 1.48 ° C MS (ES, + ion): 536 (M + H) Analysis · C35H42C I Ν302 · 1 · 8H20 Calculated value: C, 6 9.76; H, 7.29 ; N, 6.97; CI, 5 · 8 8 Measured value: C, 6 9. 7 〇; Η, 7 · 3 9; N, 7 · Ο Ο; CI, 5. 7 4 β This paper standard applies to Chinese national standard (CNS) Α4 specification (210X297 mm) (Please read the precautions on the back before filling out this page)-· " -98-486469 A7 B7 V. Description of the invention (96)

9 一〔4 一〔4 一（苯醯胺基）一 1 一哌啶基〕丁基〕一 N —丙基一 9 Η -荀一 9 一甲醯胺 熔點· 1 5 7 — 1 6 0 °C。 MS(Cj?，+ 離子）（M + H)510 分析· C33H39N3〇2· 0 · 5H20之計算值： C，76·41;Η，7·77; N，8.10 實測值：C，76.37;H，7.70;N，8.02 〇 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製9 [[4] [4 ((Benzamido)-1-piperidinyl] butyl] butyl] -N-propyl-1 9 Η-fluorene-9 9-methylamine melting point · 1 5 7 — 1 6 0 ° C. MS (Cj ?, + ion) (M + H) 510 analysis · Calculated values for C33H39N3〇2 · 0 · 5H20: C, 76 · 41; Η, 7.77; N, 8.10 Found: C, 76.37; H , 7.70; N, 8.02 〇 (Please read the notes on the back before filling out this page)

9-〔4 一〔4 一（2，3 -二氫基一 1—合氧基一 1H 一異吲跺一 2 -基）一 1 一哌啶基〕丁基〕一 N — ( 2， 2 ，2 —三氟乙基）一 9H —芴一9 一甲醯胺 熔點· 143 — 146 °C。 MS (ES，+ 離子）m/z 5 6 2 ( Μ + Η ) 分析· C33H34N3F3022計算值： 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -99 - 486469 A7 B7 五、發明説明（97 ) 〜· C，7 0 · 5 7 ; Η，6 ;F，1 0 · 1 5 實測值：C，7 0 · 0 4 ; Η，6 ;F，9 · 8 7 ° 16. 1 0 ; Ν ，7 . 4 8 8 ; Ν ，7 · 3 49- [4 a [4 a (2,3 -dihydrol-1-oxyl-1H-isoindole-2 -yl)-1-piperidinyl] butyl]-N — (2, 2 , 2-trifluoroethyl)-9H-fluorene-9-methylformamide melting point · 143-146 ° C. MS (ES, + ion) m / z 5 6 2 (Μ + Η) analysis · Calculated value of C33H34N3F3022: This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -99-486469 A7 B7 V. Invention Explanation (97) ~ · C, 7 0 · 5 7; Η, 6; F, 1 0 · 1 5 Measured value: C, 7 0 · 0 4; Η, 6; F, 9 · 8 7 ° 16. 1 0; Ν, 7. 4 8 8; Ν, 7 · 3 4

9 一〔2 -〔4一（2，3 -二氫基一 1 一合氧基一 1Η 一異蚓Ρ呆一 2 —基）一 1 一哌啶基〕乙基〕一 Ν -丙基一 9 Η —芴一 9 一甲醯胺，單氫氯酸鹽 17.9- [2-[4-((2,3-dihydrol-1) 1-oxyl-1 1-isopropylammonium-2-yl)-1-piperidinyl] ethyl] -N-propyl-1 9 Η — 芴 -9 9 methylformamide, monohydrochloride 17.

Η CH3 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 9-〔4 一〔4 一（乙醯胺基）一 1 一哌啶基〕丁基〕 N —丙基一 9 Η —荀一 9 一甲酸胺 熔點· 133- 135 °C MS(Cj^，+ 離子）（M + H)448 分析.C28H37N302· 1 · 0H2O 之計算值： C，72.23;H，8.44;N，9 實測值：C，7 1 · 9 4 ; Η，7 · 9 Ο ; Ν，8 0 2 8 8 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X 297公釐） -100 - 486469 A7 B7五、發明説明（98 ) 18·Oj-N^ N — 乙基一 9 一〔4 一〔4 - (2，3 — 二氫基-1 一合 氧基一 1 Η —異D引卩朵一 2 -基）一 1 一呢陡基〕丁基〕一 9H—芴一9一甲醯胺 、熔點.137 —140 t： MS (Cj?，M + H+ )m/z 508 + 分析。C33H37N3〇2· 0 · 29H2〇之計算值： C，77.27 ;Η，7·39;Ν，8·19 實測值·· C，7 7 · 0 5 ; Η，7 · 3 8 ; N，8 · 4 1 ο 19. (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製Η CH3 (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 9- [4 1 [4 1 (Ethylamino) 1 1 Piperidinyl] Butyl] N —Propyl-9 Η — 荀 -9 monoformic acid amine melting point · 133- 135 ° C MS (Cj ^, + ion) (M + H) 448 analysis. C28H37N302 · 1 · 0H2O Calculated value: C, 72.23; H , 8.44; N, 9 Measured value: C, 7 1 · 9 4; Η, 7 · 9 Ο; Ν, 8 0 2 8 8 This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -100-486469 A7 B7 V. Description of the invention (98) 18 · Oj-N ^ N — ethyl 9 9 [4 1 [4-(2,3 — dihydro-1 -1 monooxy 1 1 — — Iso-isocyanato- 2 -yl) -1 1-anthryl] butyl] -9H-fluorene-9-methylamine, melting point. 137 —140 t: MS (Cj ?, M + H +) m / z 508+ analysis. Calculated values for C33H37N30 2 · 0 · 29H2 0: C, 77.27; Η, 7.39; N, 8.19 Measured values · C, 7 7 · 0 5; Η, 7 · 3 8; N, 8 · 4 1 ο 19. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

9 一〔4 一〔4一（2，3 -二氫基一 1 一 合氧基-1Η 一異矧跺一 2 -基）一 1一哌啶基〕丁基〕一 N - 2，2 ，2 —三氟乙基一 9H —咕噸一 9 一甲醯胺 熔點· 164 — 166 °C (分離） 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 486469 A7 B7 五、發明説明（99 ) Μ · S' (FAB) m / z 5 7 8 ( M + H )20.9 1 [4 1 [4 1 (2,3-dihydrol-1 1-oxyl-1Η-isoiso-2-2-yl) -1 1-piperidinyl] butyl] -N -2,2, 2 —Trifluoroethyl-9H —Gutan-9 Melamine melting point · 164 — 166 ° C (separated) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) _ 486469 A7 B7 V. DESCRIPTION OF THE INVENTION (99) M · S '(FAB) m / z 5 7 8 (M + H) 20.

9 一〔4 -〔4 - ( 2，3 -二氫基一 1 一合氧基一 1H 一異吲跺一 2 —基）一 1 一哌啶基〕丁基〕一 N -丙基一 9 Η —咕噸一 9 一甲醯胺 熔點，6 2 - 6 5 °C 分析· C 3 4 Η 3 9 〇 3 N 3 + 0 . 5 Η 2 0之計算值 ： C， 7 4 .7 0 ；Η， 7 .3 7 ；Ν， 7.69 實測值’· C ， 7 4 .4 5 ；Η ， 7 .3 2 ；Ν ， 7.56 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 眚例2 1 9 一〔4 一〔4 一（2，3 -二氫基一 1 一合氧基一 1Η 一異呼跺—2 -基）一 1 一哌啶基〕丁基〕-Ν -丙基一 9 Η ^ 9 —甲酿胺，單氯氯酸鹽_；__ 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） _ 102 - 486469 A7 B7 五、發明説明（100)9- [4-[4-(2,3-dihydrol-1, 1-oxyl-1H, iso-indio-2, 2-yl), 1-piperidinyl] butyl] -N-propyl-9 Η —Gutan-9 Melamine, melting point, 6 2-6 5 ° C Analysis · C 3 4 Η 3 9 〇3 N 3 + 0.5 Calculated value of Η 2 0: C, 7 4 .7 0; Η, 7. 3 7; Ν, 7.69 measured value '· C, 7 4 .4 5; ，, 7.3.2 2; Ν, 7.56 (please read the notes on the back before filling this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperatives 2 1 9 1 [4 1 [4 1 (2,3 -dihydrol-1 1-oxyl-1 1- 1-isopropan-2-yl) -1 1-piperidinyl] D Group] -N-propyl-1 9 ^ ^ 9-methylamine, monochlorochloride _; __ This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) _ 102-486469 A7 B7 V. Invention Description (100)

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 莫耳），二異丙基乙胺（0· 4毫升，2· 31毫莫耳） 及酞酸酐（170毫克，1 . 15毫莫耳）之甲苯（3毫 升）溶液迴流5小時，而後冷卻至室溫。再將二氯甲烷（ 80毫升）加入，而後將溶液以水（2x30毫升），鹽 水（2 X 3 0毫升）清洗並於硫酸鎂上乾燥。繼而藉於矽 膠上（50克）進行急驟色層分離法，以2 · 5%甲醇之 二氯甲烷液裝填及洗提而予以純化。再結合純溶離份並予 蒸發以得白色固狀物。令所得產物溶於乙醚（5毫升）中 ，再將氫氯酸之乙_溶液（0.77莫耳濃度，2.0毫 升）加入。而後將反應於室溫下攪拌1 0分鐘，繼而蒸發 至乾、再將產物於真空爐中乾燥（5 0 °C，1 8小時）， 即得白色固狀之標題化合物（440毫克，73%)。 熔點· 1 2 5 — 1 3 0 °C。 分析· C34H38C5N303· 1 · 3H2〇 之計算值： C，68.57;H，6.87;N，7.06 ;C 又，5 · 9 5 實測值·· C，6 8 · 7 1 ; Η，6 · 6 6 ; N，7 · 0 1 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） ~ " 一 103 - 486469 A7 B7 五、發明説明（101) ” ；C 又，5 · 8 2 〇 眚例2 2 9 一〔4 一〔4 一（2，3 -二氫基一 1 一 合氧基-1H 一異口引跺一 2 -基）一 1 一哌啶基〕丁基〕一 N -丙基一 9H -益並〔2 ，l—b] —吡啶一 9-甲醯胺_ (請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling out this page) Moore printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, diisopropylethylamine (0.4 ml, 2.31 mmol) and phthalic anhydride ( A 170 mg, 1.15 mmol) toluene (3 ml) solution was refluxed for 5 hours and then cooled to room temperature. Dichloromethane (80 ml) was added, and the solution was washed with water (2 x 30 ml), saline (2 x 30 ml) and dried over magnesium sulfate. Then, it was purified by flash chromatography on silica gel (50 g), and then filled with 2.5% methanol in dichloromethane. The pure fractions were combined and evaporated to give a white solid. The obtained product was dissolved in diethyl ether (5 ml), and an acetic acid solution of hydrochloric acid (0.77 mole concentration, 2.0 ml) was added. The reaction was stirred at room temperature for 10 minutes, then evaporated to dryness, and the product was dried in a vacuum oven (50 ° C, 18 hours) to obtain the title compound (440 mg, 73%) as a white solid. ). Melting point · 1 2 5 — 1 3 0 ° C. Analysis · Calculated values for C34H38C5N303 · 1 · 3H2 0: C, 68.57; H, 6.87; N, 7.06; C, 5 · 9 5 Measured values · C, 6 8 · 7 1; Η, 6 · 6 6; N, 7 · 0 1 This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) ~ &103; 486469 A7 B7 V. Description of the invention (101) "; C, 5 · 8 2 〇 眚Example 2 2 9 1 [4 1 [4 1 (2,3-dihydrol-1 1-oxyl-1H 1-isopropyl- 2 -yl) -1 1-piperidinyl] butyl] -N- Propyl-9H-ene [2, l-b] -pyridine-9-formamide_ (Please read the precautions on the back before filling this page)

經濟部中央標準局員工消費合作社印製 將1 一氮雜一芴（233毫克，1 · 39毫莫耳；藉 已知步驟由苯並（f )喹啉中製得，Kloc, K. Journal f· prakt. Chemie, 3 1 9, 9 5 9-96 7 ( 1 9 77 )及Kloc，Κ· Heterocycles, 9, 849-852 ( 1 978 )及異氰酸正丙酯（ 0 . 13毫升，1 . 39毫莫耳）藉冷卻至一 78 °C，抽 空，令之加溫至室溫，最後以氬氣淨化而予脫氣三次。於 一 10 °C下，將雙（三甲基甲矽烷基）胺化鈉（1 · 4毫 升，1莫耳濃度之四氫呋喃液）逐滴加至脫氣溶液中。5 分鐘後，將第二份之異氰酸正丙酯（0 . 13毫升， 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） ，Λ』 一 104 _ 486469 A7 B7 五、發明説明（102) 1 · 3〜9毫莫耳）加至紅色溶液中。另1 5分鐘後，使用 飽和氯化銨令正爲綠色之反應混合物之反應中止。將水性 層以乙酸乙酯萃取，將有機相以鹽水清洗，於硫酸鈉上乾 燥及於真空中蒸發以得紅色油狀-固狀餘留物（5 3 5毫 克），再將餘留物藉急驟柱色層分離法（Si lie ΑΙΤ緩衝 化矽膠，5x7公分），以20%乙酸乙酯：二氯甲烷洗 提，及以5 %甲醇：二氯甲烷沖洗而予以純化，即得橘色 固狀之標題化合物（202毫克，58%產率）。熔點. 13 1-13 3。。。 I B. 0-SIPh2tBu (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 於18 °C (冷冰浴）下於氬下，將1 ，4 一丁二醇加 至氫化鈉（4克，60%之油分散液，0 · 10莫耳）之 四氫呋喃（1 0 0毫升）懸浮液中。於室溫下攪拌1 4小 時後，將特丁基氯碁二苯基矽烷（26毫升，0 · 1莫耳 )快滴加入，30分鐘後，使用水以令反應中止，再將水 性層以己烷萃取。繼而將有機層於硫酸鈉上乾燥並予蒸發 以得油狀物（3 3克）’再將餘留物藉急驟柱色層分離法 (矽膠，10x26公分），以二氯甲烷，5，7 . 5 ， 而後1 0%乙酸乙酯：二氯甲烷洗提而予以純化，即得無 色油狀之標題化合物（24 · 5克，74%) 。 1 〇-SIPh2t Bu 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 105 - 486469 A7 _____B7五、發明説明（1〇3) 於'·0 °c下，將碘（4 . 23克，0· 0167莫耳） 之四氫呋喃（1 5毫升）溶液於1 〇分鐘期間加至第B部 化合物（5· 48克，0.0167莫耳），三苯膦（ 4 · 3克，0 · 0164莫耳）及咪唑（2 · 49克， 0 · 0366莫耳）之四氫呋喃（70毫升）溶液中。於 室溫下1小時後，將反應冷卻至0 °C，再使用5 %水性亞 硫酸氫鈉令反應中止。而後將混合物以水及己烷稀釋，繼 而將有機層以水，飽和碳酸氫鈉，及鹽水清洗。再將有機 層於硫酸鈉上乾燥，並予蒸發以得油狀固體。將餘留物以 己烷碾磨，冷卻至0°C，過濾，再於真空中移去揮發物， 以得油狀物（7 · 3 5克），再將此餘留物藉急驟色層分 離法（Si 1 i cAR"緩衝化矽膠，5 X 1 0公分），以3 0 %二氯甲烷：己烷洗提而予以純化，即得無色油狀之標題 化合物（6 · 2克，8 4 % )。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印裝Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 1-aza-pyrene (233 mg, 1.39 mmol; prepared by known steps from benzo (f) quinoline, Kloc, K. Journal f Prakt. Chemie, 3 1 9, 9 5 9-96 7 (1 9 77) and Kloc, K · Heterocycles, 9, 849-852 (1 978) and n-propyl isocyanate (0.13 ml, 1 39 millimoles) by cooling to a temperature of 78 ° C, evacuating, warming to room temperature, and finally degassing three times with argon purification. At a temperature of 10 ° C, bis (trimethylsilane) Base) sodium amide (1.4 ml, tetrahydrofuran solution at 1 mole concentration) was added dropwise to the degassed solution. After 5 minutes, a second portion of n-propyl isocyanate (0.13 ml, this Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm), Λ′-104_486469 A7 B7 V. Description of the invention (102) 1 · 3 ~ 9 millimoles) added to the red solution. Another After 15 minutes, the reaction of the green reaction mixture was stopped with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, the organic phase was washed with brine, and dried over sodium sulfate. And evaporated in vacuo to obtain a red oily-solid residue (5 3 5 mg), and then the residue was subjected to flash column chromatography (Si lie ΑΙΤ buffered silicone, 5x7 cm), at 20% Ethyl acetate: dichloromethane was eluted and purified by washing with 5% methanol: dichloromethane to obtain the title compound (202 mg, 58% yield) as an orange solid. Melting point. 13 1-13 3 ... I B. 0-SIPh2tBu (Please read the precautions on the back before filling this page) Printed at 18 ° C (cold ice bath) under argon by the Consumer Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs. 4 Monobutylene glycol was added to a suspension of sodium hydride (4 g, 60% in oil dispersion, 0.1 mol) in tetrahydrofuran (100 ml). After stirring at room temperature for 14 hours, the special Butylchlorophosphonium diphenylsilane (26 ml, 0.1 mol) was added dropwise. After 30 minutes, water was used to stop the reaction, and the aqueous layer was extracted with hexane. The organic layer was then applied over sodium sulfate. Dried and pre-evaporated to get an oil (33 g). Then the residue was separated by flash column chromatography (silica gel, 10x26 cm) with dichloromethane. Alkane, 5,7.5, and then purified by elution with 10% ethyl acetate: dichloromethane to obtain the title compound (24. 5 g, 74%) as a colorless oil. 10-SIPh2t Bu Paper The scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 105-486469 A7 _____B7 V. Description of the invention (103) At '· 0 ° c, the iodine (4.23 g, 0.067) Tetrahydrofuran (15 ml) solution was added to Part B compound (5.48 g, 0.0167 mole), triphenylphosphine (4.3 g, 0. 0164 mole) and imidazole in 10 minutes (2.49 g, 0.0366 moles) in tetrahydrofuran (70 ml). After 1 hour at room temperature, the reaction was cooled to 0 ° C and the reaction was stopped with 5% aqueous sodium bisulfite. The mixture was then diluted with water and hexane, and the organic layer was washed with water, saturated sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and pre-evaporated to give an oily solid. The residue was triturated with hexane, cooled to 0 ° C, filtered, and the volatiles were removed in a vacuum to obtain an oil (7.55 g), which was then borrowed from the flash layer Separation (Si 1 i cAR " buffered silicone, 5 X 10 cm), purified by extraction with 30% dichloromethane: hexane, to give the title compound as a colorless oil (6.2 g, 8 4%). (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs

將第A部化合物（400毫克，1 · 58毫莫耳）之 四氫呋喃（9毫升）溶液藉冷卻至一 7 8°C，抽空，令之 加溫至室溫，最後以氬氣淨化而予脫氣三次。於0 °C下， 將正丁基鋰（1 · 3毫升，2 · 5莫耳濃度之己烷液）逐 滴加至脫氣溶液中。數分鐘後，將第C部化合物（ f紙張尺度適用中國國家標準（ CNS ) A4規格（210X297公釐）_ - 486469 A7 ____B7_ 五、發明説明（104) 0 . 毫升，1 · 8 2毫莫耳）加至紅色溶液中。另1 小時後使用飽和氯化銨以令正爲棕色之反應混合物之反應 中止。再將水性層以乙酸乙酯萃取兩次，繼而將有機相於 硫酸鈉上乾燥，及於真空中蒸發以得橘色油狀物（ 1 · 07克）。再將餘留物藉急驟柱色層分離法（ Si li cAR"緩衝化矽膠，5 X 8 · 5公分），以8 %乙酸 乙酯：二氯甲烷洗提而予以純化，即得無色油狀之標題化 合物（817毫克，92%)。 (請先閲讀背面之注意事項再填寫本頁)A solution of the compound in Part A (400 mg, 1.58 mmol) in tetrahydrofuran (9 ml) was cooled to 778 ° C, evacuated, allowed to warm to room temperature, and finally purified by argon purification. Gas three times. At 0 ° C, n-butyllithium (1.3 ml, 2.5 moles of hexane) was added dropwise to the degassed solution. After a few minutes, apply the Part C compound (f paper size to the Chinese National Standard (CNS) A4 specification (210X297 mm) _-486469 A7 ____B7_ V. Description of the invention (104) 0. ml, 1. 8 2 millimoles ) To the red solution. After another 1 hour, saturated ammonium chloride was used to stop the reaction of the brown reaction mixture. The aqueous layer was extracted twice with ethyl acetate, and the organic phase was dried over sodium sulfate and evaporated in vacuo to give an orange oil (1.07 g). The residue was purified by flash column chromatography (Si li cAR " buffered silica gel, 5 X 8 · 5 cm), and purified by eluting with 8% ethyl acetate: dichloromethane to obtain a colorless oil. The title compound (817 mg, 92%). (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 將四丁銨化氟（1 · 5毫升，1莫耳濃度之四氫呋喃 液）逐滴加至於氬氣下之第D部化合物（8 0 0毫克， 1 · 42毫莫耳）之四氫呋喃（3 · 5毫升）溶液中。2 小時後，將第二份四丁銨化氟（0 · 15毫升，1莫耳濃 度之四氫呋喃液）加入，再令反應混合物攪拌另1小時。 繼而令反應混合物分界於水及乙酸乙酯間。再將水性層以 乙酸乙酯萃取3次，並將有機相以鹽水清洗。第一個有機 層乃含有少量銨鹽，將其於硫酸鈉上乾燥，及於真空中蒸 發以得油狀物（8 8 5毫克）。再將餘留物藉急驟柱色層 分離法（SilicAlT緩衝化矽膠，9 0克），以4 . 5% 甲醇：二氯甲烷洗提而予以純化，即得無色固狀之標題化 合物（4 3 7毫克，9 5 % )。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 1〇7 _ "' 486469 A7 ____B7五、發明説明（l〇5 )Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Tetrabutylammonium fluoride (1.5 ml, tetrahydrofuran solution at 1 mole concentration) was added dropwise to the D-part compound (800 mg, 1 42 mmol) in tetrahydrofuran (3.5 ml). After 2 hours, a second portion of tetrabutylammonium fluoride (0.15 ml, 1 mole of tetrahydrofuran solution) was added, and the reaction mixture was stirred for another 1 hour. The reaction mixture was then delimited between water and ethyl acetate. The aqueous layer was extracted three more times with ethyl acetate, and the organic phase was washed with brine. The first organic layer contained a small amount of ammonium salt, which was dried over sodium sulfate and evaporated in vacuo to give an oil (85 mg). The residue was purified by flash column chromatography (SilicAlT buffered silica gel, 90 g) and purified by eluting with 4.5% methanol: dichloromethane to obtain the title compound as a colorless solid (4 3 7 mg, 95%). This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 1〇7 _ " '486469 A7 ____B7 V. Description of the invention (105)

經濟部中央標準局員工消費合作社印製 毫克，0 . 8 60毫莫耳）加至第E部化合物（23 1毫 克，0，712毫莫耳）及三苯膦（285毫克， 1 · 09毫莫耳）之二氯甲烷（5毫升）溶液中》 2 · 1 5小時後，將第二份N -溴基琥珀醯亞胺（1 8毫 克，0 · 101毫莫耳）加入，再將反應於〇°C下攙拌 4 5分鐘及於室溫下1 5分鐘。繼而使用1 〇%亞硫酸氫 鈉令反應混合物中止，再將水性層以二氯甲烷萃取兩次。 而後將結合之有機相以鹽水清洗，於硫酸鈉上乾燥，及於 真空中蒸發以得油狀-固狀餘留物（6 5 3毫克）》再將 餘留物藉急驟柱色層分離法（Si licAlT緩衝化矽膠， 68克），以10·. 5%乙酸乙酯：二氯甲烷洗提而予以 純化，即得無色油狀之標題化合物（2 17毫克，78% )° G ·Printed in milligrams by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, 0.860 millimoles) added to Part E compounds (23 1 milligrams, 0,712 millimoles) and triphenylphosphine (285 milligrams, 1.09 millimoles Mol) in dichloromethane (5 ml) solution. After 2 · 15 hours, add a second portion of N-bromosuccinimide (18 mg, 0 · 101 mmol), and then add the reaction. Stir for 45 minutes at 0 ° C and 15 minutes at room temperature. The reaction mixture was then quenched with 10% sodium bisulfite, and the aqueous layer was extracted twice with dichloromethane. The combined organic phases were then washed with brine, dried over sodium sulfate, and evaporated in vacuo to obtain an oily-solid residue (653 mg). The residue was then separated by flash column chromatography. (SilicicT buffered silica gel, 68 g), purified by elution with 10. · 5% ethyl acetate: dichloromethane to give the title compound as a colorless oil (2 17 mg, 78%) ° G ·

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-i〇8 一 (請先閲讀背面之注意事項再填寫本頁) 訂 486469 A7 B7 五、發明説明（106) 於氬下，將碳酸鉀（65毫克，〇· 47毫莫耳）加 至第F部化合物（180毫克，0 · 465毫莫耳）及實 例1第G部化合物（135毫克，〇 · 624毫莫耳）之 二甲基甲醯胺（1 · 6毫升）溶液中。18 · 15小時後 ，令紫色反應分界於稀碳酸氫鈉及乙酸乙酯間。再將水性 層以乙酸乙酯萃取兩次，而後將結合之有機相以水，鹽水 清洗，於硫酸鈉上乾燥，再於真空中移去揮發物以得紫色 油狀物（2 3 0弯克）。繼而將餘留物藉急驟柱色層分離 法（SilicAR"緩衝化矽膠，2 6 · 5克），以5%而後 6 %甲醇：二氯甲烷洗提而予以純化，即得無色泡沬狀之 標題化合物（8 3毫克，34%產率）。標題化合物另以 混合物形式獲得（9 6毫克，藉高效能液體色層分離法得 知爲9 2 %純度，7 2 %產率）。 熔點· 5 2 - 5 4 °C。 M S ：(電噴霧，Μ + Η+ ) :m/z 523+。 實例2 3 經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 2，3 -二氫基一 2 -〔 1 一〔4 一 羥基一 4 一（ 9 一丙 基一 9H -芴-9 一基〕丁基〕一 4 一哌啶基〕一 1H — 異吲跺一 1 一酾1_ 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 1〇9 _ 486469 A7 B7 五、發明説明（1〇7)This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) -i〇8 I (Please read the notes on the back before filling this page) Order 486469 A7 B7 V. Description of the invention (106) Under argon, Potassium carbonate (65 mg, 0.47 mmol) was added to the compound of Part F (180 mg, 0.465 mmol) and the compound of Part G of Example 1 (135 mg, 0.624 mmol) Dimethylformamide (1.6 ml) in solution. After 18 · 15 hours, the purple reaction was delimited between dilute sodium bicarbonate and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and then the combined organic phases were washed with water, brine, dried over sodium sulfate, and the volatiles were removed in vacuo to give a purple oil (230 ). The residue was then purified by flash column chromatography (SilicAR " buffered silica gel, 26.5 g), and then purified by eluting with 5% and then 6% methanol: dichloromethane to obtain a colorless foam. The title compound (83 mg, 34% yield). The title compound was obtained as a mixture (96 mg, 92% purity, 72% yield by high performance liquid chromatography). Melting point · 5 2-5 4 ° C. M S: (electrospray, M + Η +): m / z 523+. Example 2 3 Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 2,3 -dihydrol 2-[1 1 [4 -hydroxyl 4 4 (9 1 Propyl-9H-fluoren-9-yl] butyl] -4piperidinyl] -1H — isoindole-1 1 酾 1_ This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1 1〇_ 486469 A7 B7 V. Description of the invention (1〇7)

經濟部中央標隼局員工消費合作社印製 0 · 6 1毫莫耳）之1 2毫升甲醇溶液冷卻至0°c，再將 2當量氫硼化鈉（48 · 5毫克，1 · 28毫莫耳）加入 。而後將反應混合物於0°C下攪拌4 5分鐘。繼而使用1 當量濃度氫氯酸令反應中止，再以乙酸乙酯（3 X 2 0毫 升）萃取。而後將萃取液以鹽水清洗及於硫酸鈉上乾燥。 令蒸發後所得之油狀餘留物溶於二氯甲烷中，於硫酸鈉上 乾燥再予蒸發以得5 5 0毫克無色固狀物。繼而將粗製產 物藉於Merck EM矽膠柱上以5 %甲醇/二氯甲烷洗提而予 以純化，即得2 9 0毫克（9 6%)無色固狀之標題化合 物。 熔點。7 5 — 78°C。 MS(CI)m/z 495 (M + H)。 實例2 4 2 ’ 3 -二氫基一 2 —〔1一〔3 -〔（9 一 丙基一 9一 芴一 9 一基）硫代〕丙基〕一 4 一哌啶基〕一 1H —異口引 卩朵—1 一酮___ 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 11〇 一 (請先閲讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（1〇8)Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 1.2 ml of methanol solution was cooled to 0 ° C, and 2 equivalents of sodium borohydride (48.5 mg, 1.28 mmol) Ear) join. The reaction mixture was then stirred at 0 ° C for 4 5 minutes. The reaction was then stopped using 1 equivalent of hydrochloric acid and extracted with ethyl acetate (3 X 20 mL). The extract was washed with brine and dried over sodium sulfate. The oily residue obtained after evaporation was dissolved in dichloromethane, dried over sodium sulfate and then evaporated to obtain 550 mg of a colorless solid. The crude product was purified by elution on a Merck EM silica gel column with 5% methanol / dichloromethane to give 290 mg (9 6%) of the title compound as a colorless solid. Melting point. 7 5 — 78 ° C. MS (CI) m / z 495 (M + H). Example 2 4 2 '3 -dihydrol-2 — [1— [3-[(9-propyl-9-fluoren-9-yl) thio] propyl] -4 4-piperidinyl] -1H— Indifferent words—1 monoketone___ This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm)-1101 (Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (108)

〇6〇 A.〇6〇 A.

，於氬下，將正丙基鎂化氯（25 · 4 之乙醚液）逐滴加至芴一 9 一酮（ 於一 1 毫升，2莫 9 · 1 2 克 )溶液中。 混合物之反 有機相以鹽 得油狀-固 0 0C下 耳濃度，0 . 1 . 1 應中止 水清洗 狀餘留 經濟部中央標準局員工消費合作社印製 醇：水中結晶而予 量％9-羥基一芴 此物質乃具有充分 B. 05 1莫耳）之四氫呋喃（1 00毫升 5小時後，使用飽和氯化銨令橘色反應 。再將水性層以乙酸乙酯萃取兩次，將 ，於硫酸鈉上乾燥，及於真空中蒸發以 物（11 · 1克）^再將餘留物藉由乙 以純化，即得無色固狀之沾染有1 4重 之標題化合物（4克，3 0%產率）〇 純度以供接續之反應所用。Under argon, n-propylmagnesium chloride (diethyl ether solution of 25.4) was added dropwise to a solution of fluorene-9-one (in 1 ml, 2 mol 9.12 g). The anti-organic phase of the mixture is oily with salt-solid 0 0C lower ear concentration, 0.1. 1 should be discontinued. Water should be left. The alcohol printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: crystallized in water and a certain amount. The hydroxy group was tetrahydrofuran (100 ml, 5 hours) with sufficient B. 05 1 mole. After 5 hours, saturated orange was reacted with saturated ammonium chloride. The aqueous layer was extracted twice with ethyl acetate, and Dry over sodium sulfate and evaporate the residue in vacuum (11.1 g) ^ and purify the residue with ethyl acetate to obtain a colorless solid contaminated with 14 weight of the title compound (4 g, 3 0 % Yield) o Purity for subsequent reactions.

於氬下，將濃硫酸（7滴）加至第A部化合物 (請先閲讀背面之注意事項再填寫本頁)Add concentrated sulfuric acid (7 drops) to Part A compound under argon (please read the precautions on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）一 m 486469 A7 ____B7 五、發明説明（1〇9) 3 . 克，0 · 0 1 4莫耳）及3 —酼基丙酸甲酯（ 1 · 62毫升，0 · 015莫耳）之乙酸（25毫升）溶 液中。於室溫下攪拌2 4小時後，將反應濃縮成原始量之 1/3，再以水稀釋。繼而將水性層以乙酸乙酯萃取，再 將有機層以1當量濃度氫氧化鈉清洗。將鹼性清洗液以乙 酸乙酯萃取3次，將結合之有機相以鹽水萃取，於硫酸鈉 上乾燥並予蒸發，以得油狀-固狀之結構（B 1 )This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm)-m 486469 A7 ____B7 V. Description of the invention (1 09) 3 grams, 0 · 0 1 4 moles) and 3-hydrazone Methyl acetate (1.62 ml, 0. 015 mol) in acetic acid (25 ml). After stirring at room temperature for 24 hours, the reaction was concentrated to 1/3 of the original amount, and then diluted with water. Then, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with 1 equivalent of sodium hydroxide. The alkaline cleaning solution was extracted three times with ethyl acetate, and the combined organic phase was extracted with brine, dried over sodium sulfate, and evaporated to obtain an oil-solid structure (B 1).

OMe (請先閲讀背面之注意事項再填寫本頁) (5 · 5 5 克： 績之反應所用。Rf = 0· 49 (25%乙酸乙酯：己烷 )° 經濟部中央標隼局負工消費合作社印製 將氫硼化鈉（470毫克，0 · 0 1 2莫耳）加至化 合物B(l)(385毫克，0.956毫莫耳）之乙醇 (1 5毫升）溶液中。攪拌過夜後，將反應混合物冷卻至 0°C，再使用飽和氯化銨令反應中止。而後將水性層以乙 酸乙酯萃取，將有機層以鹽水清洗，於硫酸鈉上乾燥並予 蒸發成油狀餘留物（3 9 0毫克）。再將此餘留物藉急驟 柱色層分離法（矽膠，3x10公分），以3%乙酸乙酯 :二氯甲烷洗提而予以純化，即得無色油狀之標題化合物 (110毫克，由第A部化合物中得到38%產率）。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 112 486469 A7 ___B7 五、發明説明（110 )OMe (Please read the notes on the back before filling this page) (5 · 5 5 g: used for the reaction of R. Rf = 0 · 49 (25% ethyl acetate: hexane) ° Work of the Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperative Sodium borohydride (470 mg, 0.012 mol) was added to a solution of compound B (l) (385 mg, 0.956 mmol) in ethanol (15 ml). After stirring overnight The reaction mixture was cooled to 0 ° C and the reaction was stopped with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate and evaporated to an oily residue. (390 mg). The residue was purified by flash column chromatography (silica gel, 3x10 cm) and extracted with 3% ethyl acetate: dichloromethane to obtain a colorless oil. Title compound (110 mg, 38% yield from the compound of Part A). This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 112 486469 A7 ___B7 5. Description of the invention (110)

(請先閲讀背面之注意事項再填寫本頁) 訂 於0°C下，將對位甲苯磺醯氯（80毫克，0 · 42 毫莫耳）加至第B部化合物（11〇毫克，〇。369毫 莫耳）之吡啶（0 · 7 5毫升）溶液中，再令反應徐緩回 至室溫。4小時及7 · 5小時後，將另外之對位甲苯磺醯 氯（60，而後40毫克，0 · 5 2亳莫耳）於室溫下加 入，再將反應於5 °C下攪拌過夜。而後將最後一份對位甲 苯磺醯氯（40毫克，共1 · 15毫莫耳）加入，再將反 應於室溫下攪拌8小時。繼而令反應混合物分界於乙酸乙 酯及飽和碳酸氫鈉間。再將水性層以乙酸乙酯萃取3次， 將有機層以鹽水清洗，於硫酸鈉上乾燥並予蒸發成油狀-固體（200毫克）。將此餘留物預吸附於寅氏鹽上，再 藉急驟柱色層分離法（砂膠，3 X 8公分），以1 5%乙 酸乙酯：己烷洗提而予以純化，即得無色油狀之標題化合 經濟部中央標隼局員工消費合作社印製 o C 1 第 1 將 /1\ 物(Please read the precautions on the back before filling this page) At 0 ° C, add p-toluenesulfonyl chloride (80 mg, 0.42 mmol) to the compound in Part B (11 mg, 〇 (369 mmol) in pyridine (0.75 ml), and the reaction was allowed to slowly return to room temperature. After 4 hours and 7 · 5 hours, additional p-toluenesulfonyl chloride (60, then 40 mg, 0.52 mol) was added at room temperature, and the reaction was stirred at 5 ° C overnight. The last portion of p-toluenesulfonyl chloride (40 mg, total of 1.15 mmol) was added, and the reaction was stirred at room temperature for 8 hours. The reaction mixture was then delimited between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted three more times with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate and pre-evaporated to an oily-solid (200 mg). This residue was pre-adsorbed on Yin's salt, and then purified by flash column chromatography (sand gel, 3 X 8 cm), and then purified by elution with 15% ethyl acetate: hexane to obtain colorless. Oily title printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs o C 1 No. 1/1

耳 莫 毫 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 113 486469 A7 B7 五、發明説明（111 ) ，實例71第G部化合物（64毫克，0· 296毫莫耳） 及碳酸鉀（34毫克，0 · 246毫莫耳）之異丙醇（ 1 · 5毫升）混合液於氬下迴流6小時。冷卻後，令反應 分界於飽和碳酸氫鈉及乙酸乙酯間。再將水性層以乙酸乙 酯萃取兩次，而後將結合之有機相於硫酸鈉上乾燥，再於 真空中移去揮發物以得油狀物（126毫克）。將餘留物 與使用4 8 · 6毫莫耳第C部化合物由相同反應中所得之 另一粗製餘留物結合（共14 6毫克）。再將混合物藉急 驟柱色層分離法（矽膠，3x5 · 5公分），以4%甲醇 :二氯甲烷洗提而予以純化，以得不純之標題化合物（ 1 0 8毫克）。將此混合物藉急驟柱色層分離法（矽膠， 1 2克），以4 %甲醇：二氯甲烷洗提而更進一步純化， 即得油狀泡沬之標題化合物（1 0 1毫克，7 4 %產率） 〇 MS (電噴霧，M + H+ ) :m/z 497 +。 分析· C32H36N2.OS · 〇 · 26Η20 之計算值： 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) C，76 ·64;Η，7.34; Ν，5.59 實測值：C，7 6 · 7 3 ; Η，7 · 2 7 ; Ν，5 · 5 1 實例2 5 2，3 -二氫基一 2-〔1一〔3 —〔 （9 一 丙基一 9Η 一芴一 9 一基）磺醯〕丙基〕一 4 一哌啶基〕一 1Η —異 崎皎一1一酮_ 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐），,< -114- 486469 Α7 Β7 五、發明説明（112 )Ermo mill This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 113 486469 A7 B7 V. Description of the invention (111), Example 71 Part G compound (64 mg, 0.296 millimolar) And potassium carbonate (34 mg, 0.246 mmol) in isopropanol (1.5 ml) was refluxed under argon for 6 hours. After cooling, the reaction was delimited between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic phases were dried over sodium sulfate and the volatiles were removed in vacuo to give an oil (126 mg). The residue was combined with another crude residue obtained from the same reaction using 4 8 · 6 mmol of Part C compound (a total of 14 6 mg). The mixture was purified by flash column chromatography (silica gel, 3x5 · 5 cm), and eluted with 4% methanol: dichloromethane to obtain the impure title compound (108 mg). This mixture was further purified by flash column chromatography (silica gel, 12 g) and eluted with 4% methanol: dichloromethane to obtain the title compound (101 mg, 7 4) as an oily foam. % Yield) MS (electrospray, M + H +): m / z 497+. Analysis · C32H36N2.OS · Calculated value of 26Η20: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) C, 76 · 64; Η, 7.34; Ν, 5.59 Measure Values: C, 7 6 · 7 3; Η, 7 · 2 7; Ν, 5 · 5 1 Example 2 5 2, 3 -dihydro-1,2- [1- [3 — [(9-propyl-9Η 1 芴 1 9 一) sulfonyl] propyl]〕 4 一 piperidinyl] 一 1Η —Isogasaki-11one_ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ,, < -114- 486469 Α7 Β7 V. Description of the invention (112)

〇6〇 A,〇6〇 A,

經濟部中央標隼局員工消費合作社印裝Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

於氬 物（3 · (1.6 溶液中。 之1 / 3 再將有機 液以乙酸 硫酸鈉上 >10 0 於0 克，6 · (1克， 中，再令 將另外之 克，共9 一 8 0 〇C 下，將濃硫 6 4 克，0 2毫升，0 於室溫下攪 ，再以水稀 層以1當量 乙酯萃取3 乾燥，再蒸 %回收率） °C下，於氬 1 3毫莫耳 2 · 6 3 毫 溶液回至室 3 -氣基過 .3 9毫莫 下。加溫後 酸（7滴）加至實例2 4第A部化合 • 〇 1 4莫耳）及3 -锍基丙酸甲酯 • 015莫耳）之乙酸（25毫升） 拌2 4小時後，將反應濃縮成原始量 釋。而將將水性層以乙酸乙酯萃取， 濃度氫氧化鈉清洗。繼而將鹼性清洗 次，將結合之有機相以鹽水萃取，於 發成油狀一固體（5 .55克， 〇 下，將3 -氯基過苯甲酸（1.41 ，7 5 % )加至以上所製粗製化合物 莫耳）之二氯甲烷（2 5毫升）溶液 溫。1 · 4 5，4 · 1及6小時後， 苯甲酸（0·25，0·3及0.2 耳）加入。8小時後將反應貯存於 ，令反應混合物分界於1當量濃度氫 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） -115 - 486469 A7 ____B7__ 五、發明説明（113) 氧化鈉汲乙酸乙酯間。再將水性層以乙酸乙酯萃取兩次， 將有機層以鹽水清洗，於硫酸鈉上乾燥，並蒸發成油狀-固狀餘留物。再將餘留物藉急驟柱色層分離法（矽膠，5 X 9公分），以1 8 %乙酸乙酯：己烷洗提而予以純化， 即得無色固狀之標題化合物（6 3 0毫克，由實例2 4第 A部化合物中得到67%產率）。熔點.74 - 77 °C。 分析· C2〇H22S〇4· 0 · 29H2〇之計算值： C，6 6.04;H，6.26;S，8.81 實測值：C，6 6 · 0 4 ; Η，6 · 1 1 ; S，8 · 4 5 (請先閲讀背面之注意事項再填寫本頁)In argon (3 · (1.6 solution. 1/3 of the organic solution was then sodium sulfate acetate> 10 0 to 0 g, 6 · (1 g, medium, and then another 9 g, a total of 9 1 At 800 ° C, 64 g of concentrated sulfur, 0.2 ml, 0 were stirred at room temperature, and then the mixture was extracted with 1 equivalent of ethyl acetate in a thin layer of water, dried, and then evaporated at% recovery rate at ° C under argon. 1 3 mM 2 · 6 3 mM solution returned to the chamber 3-Air base. 3 9 mM. After heating, the acid (7 drops) was added to Example 2 4 Part A compound • 〇 1 4 mol) And methyl 3-methylpropionate • 015 mol) in acetic acid (25 ml). After stirring for 2 4 hours, the reaction was concentrated to the original volume release. The aqueous layer was extracted with ethyl acetate and washed with concentrated sodium hydroxide. Then, the alkaline washing was performed twice, and the combined organic phase was extracted with brine, and a solid (5.55 g, 0.5%) was added to 3-chloroperbenzoic acid (1.41, 75%) to the above. A solution of the obtained crude compound (Mole) in dichloromethane (25 ml) was warmed. After 1 · 4 5, 4 · 1 and 6 hours, benzoic acid (0 · 25, 0.3 and 0.2 ears) was added. After 8 hours, store the reaction in such a way that the reaction mixture delimits at 1 equivalent concentration of hydrogen (please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) Α4 specification (210 × 297 mm) -115- 486469 A7 ____B7__ 5. Description of the invention (113) Sodium oxide is extracted between ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and evaporated to an oily-solid residue. The residue was purified by flash column chromatography (silica gel, 5 X 9 cm) and extracted with 18% ethyl acetate: hexane to obtain the title compound (630 mg as a colorless solid). , 67% yield was obtained from the compound of Example 24, Part A). Melting point .74-77 ° C. Analysis · Calculated values of C2〇H22S04 · 0 · 29H2〇: C, 6 6.04; H, 6.26; S, 8.81 Found: C, 6 6 · 0 4; Η, 6 · 1 1; S, 8 · 4 5 (Please read the notes on the back before filling this page)

經濟部中央標隼局員工消費合作社印製 3 · 36毫莫耳）加至第Α部化合物（5 59毫克， 1 · 56毫莫耳）之乙醇（14毫升）懸浮液中，再令混 合物回至室溫。1小時後，將反應混合物冷卻至0°C，再 將第二份氫硼化鈉（80毫克，3 · 36毫莫耳）加入。 於室溫下5小時後，使用飽和氯化銨將反應混合物之反應 於0°C下中止，再將混合物於室溫下攪拌3 0分鐘。繼而 將水性層以乙酸乙酯萃取兩次，再將結合之有機層蒸發成 油狀餘留物。而後將此餘留物與甲醇共同蒸發3次以得 5 0 0毫克油狀-固狀。預吸附於寅氏鹽上後，將餘留物 本紙張尺度適用中國國家標準（CNS )A4規格（ 210X297公釐）_ 116 _ ' 46 6 8 A7 ____^_JB7^ 五、發明説明（114) 藉急驟驻色層分離法（矽膠，5x7公分），以3%甲醇 :二氯甲烷洗提而予以純化，即得無色固狀之標題化合物 (328毫克，64%產率）。熔點· ill · 5 - 1 1 2。5 °C。 c.Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 3.36 mmoles, and added to a suspension of the compound of Part A (5 59 mg, 1.56 mmoles) in ethanol (14 ml). To room temperature. After 1 hour, the reaction mixture was cooled to 0 ° C and a second portion of sodium borohydride (80 mg, 3.36 mmol) was added. After 5 hours at room temperature, the reaction of the reaction mixture was stopped using saturated ammonium chloride at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. The aqueous layer was then extracted twice with ethyl acetate, and the combined organic layers were evaporated to an oily residue. Then, the residue was co-evaporated 3 times with methanol to obtain 500 mg of an oily-solid state. After pre-adsorption on Yin's salt, the paper size of the residue is applied to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 116 _ '46 6 8 A7 ____ ^ _ JB7 ^ V. Description of the invention (114) Flash chromatography (silica gel, 5x7 cm) was purified by eluting with 3% methanol: dichloromethane to give the title compound (328 mg, 64% yield) as a colorless solid. Melting point · ill · 5-1 1 2.5 ° C. c.

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 於〇°C下，於氬下，將N —溴基琥珀醯亞胺（21 〇 毫克，1 · 18毫莫耳）加至第B部化合物（308毫克 ，0 · 933毫莫耳）及三苯膦（490毫克，1 · 87 毫莫耳）之二氯甲烷（5毫升）溶液中。2小時後，將第 二份N -溴基琥珀醯亞胺（40毫克，0 · 34毫莫耳） 加入，再將反應攪拌另1小時。繼而使用1 〇%亞硫酸氫 鈉以令反應混合物之反應中止，再將水性層以乙酸乙酯萃 取兩次。而後將結合之有機相以水，鹽水清洗，於硫酸鈉 上乾燥及於真空中蒸發以得油狀-固狀餘留物。再將餘留 物藉急驟柱色層分離法（Si 1 icAR"緩衝化矽膠，5 X 9 公分），以6. 7%己烷··二氯甲烷，而後二氯甲烷洗提 而予以純化，即得無色固狀之結構爲(Please read the precautions on the back before filling out this page) The Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, printed at 0 ° C and argon. 18 millimoles) to a solution of Part B compound (308 mg, 0.933 millimoles) and triphenylphosphine (490 mg, 1.87 millimoles) in dichloromethane (5 mL). After 2 hours, a second portion of N-bromosuccinimide (40 mg, 0.34 mmol) was added and the reaction was stirred for another 1 hour. Subsequently, 10% sodium bisulfite was used to stop the reaction of the reaction mixture, and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were then washed with water, brine, dried over sodium sulfate and evaporated in vacuo to give an oily-solid residue. The residue was purified by flash column chromatography (Si 1 icAR " buffered silica gel, 5 X 9 cm) with 6.7% hexane ·· methylene chloride, and then purified by dichloromethane elution. The colorless solid structure is

之不安定化合物C(l) (283毫克，77%產率）。 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）二~ 486469 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（115) 熔點 - 8 6 °C。 於氬下，將化合物C(l) (234毫克， 0 · 595毫莫耳）及實例1第G部化合物（155毫克 ’ 0 · 717毫莫耳）之二甲基甲醯胺（2毫升）溶液攪 拌1 5小時。而後將第二份實例1第G部化合物（1 7毫 克，0…0 7 8毫莫耳）加入，4小時內再將碳酸鉀（ 33毫克，0 · 239毫莫耳）加入。24小時後，令冷 卻之反應混合物分界於飽和碳酸氫鈉及乙酸乙酯間。再將 水性層以乙酸乙酯萃取，將有機相以鹽水清洗，於硫酸鈉 上乾燥，而後於真空中移去揮發物以得油狀物（3 5 7毫 克），再將聚合物藉急驟柱色層分離法（矽膠，3x 12。5公分），以5%甲醇：二氯甲烷洗提而予以純化 以得不純之標題化合物（2 2 2毫克），以及純標題化合 物（76毫克，沾染10%二甲基甲醯胺）。將純標題化 合物由乙酸乙酯：己烷中結晶，即得無色固狀之標題化合 物（3 9毫克）。將不純之標題化合物藉急驟柱色層分離 法（矽膠，24克），以5%甲醇：二氯甲烷洗提而予以 更進一步純化，即得標題化合物（1 5 3毫克，共1 9 2 毫克，61%產率）。熔點分解· 138 - 141 °C。 MS:(電噴霧，M + H+ ) ： m / z 529+。 分析· C32H3eN 2 03S · 1 · 〇1H20 之計算值： C，70·29;Η，7·01; N，5.12 實測值：C，70.45;H，6.60;N，4.96 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ，，〇 -11〇 (請先閲讀背面之注意事項再填寫本頁)Unstable compound C (l) (283 mg, 77% yield). This paper size applies to China National Standard (CNS) A4 (210X297 mm) II ~ 486469 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (115) Melting point-8 6 ° C. Under argon, dimethylformamide (2 mL) of compound C (l) (234 mg, 0. 595 mmol) and the compound of Part 1 of Example 1 (155 mg '0.717 mmol) The solution was stirred for 15 hours. Then, a second portion of the compound of Example 1, Part G (17 mg, 0 ... 0 78 mmol) was added, and potassium carbonate (33 mg, 0.239 mmol) was added within 4 hours. After 24 hours, the cooled reaction mixture was delimited between saturated sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate, and the volatiles were removed in vacuo to give an oil (357 mg), and the polymer was passed through a flash column Chromatographic separation (silica gel, 3x 12.5 cm), purified by extraction with 5% methanol: dichloromethane to obtain the impure title compound (2.2 mg), and the pure title compound (76 mg, stained 10) % Dimethylformamide). The pure title compound was crystallized from ethyl acetate: hexane to give the title compound (39 mg) as a colorless solid. The impure title compound was further purified by flash column chromatography (silica gel, 24 g) and eluted with 5% methanol: dichloromethane to obtain the title compound (153 mg, 192 mg total). , 61% yield). Melting point decomposition: 138-141 ° C. MS: (electrospray, M + H +): m / z 529+. Analysis · Calculated values of C32H3eN 2 03S · 1 · 〇1H20: C, 70 · 29; Η, 7.01; N, 5.12 Found: C, 70.45; H, 6.60; N, 4.96 This paper standard applies to Chinese national standards (CNS) A4 specification (210X297mm), 〇-11〇 (Please read the precautions on the back before filling this page)

、1T 486469 Α7 Β7 五、發明説明（116) 實例2 61T 486469 Α7 Β7 V. Description of the invention (116) Example 2 6

2 ’ 3 —二氫基一 1 一〔4 一〔4— (2，3〜〜每甘 *~凰基一 1 一合氧基一 1H -異蚓跺一 2 —基）一 1 一呢唆基〕丁 經濟部中央標隼局員工消費合作社印製 基〕一 N—丙某一 1 Η —芘一 1 一甲醯胳__ 一 ' —___ I CONHCH2CH2CH3Οό—~~^—— 於室溫下，於氬下，將15 · 0毫升草醯氯溶液（ 3 0 · 0毫莫耳，2莫耳濃度之二氯甲烷液），而後將 0·1毫升二甲基甲醯胺加至已攪拌之 C〇2卩 (―⑺丨 (3 · 20克’ 20 · 0毫莫耳）之20毫升二氯甲院獎 液中。強烈氣體釋出後可得淡黃色溶液。1小時後，# & 應混合物於小於2 5 °C之溫度下蒸發，再令餘留物溶於 10毫升四氫呋喃中。 繼而於一 1 0 °C下，於氬下，將此溶液於1 5分鐘期 間逐滴加至3 · 5毫升正丙胺（46毫莫耳）之2 5毫升 四氫呋喃中。一小時後，令反應混合物分界於乙酸乙酯及 (請先閲讀背面之注意事項再填寫本頁) 言 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐）、，Λ -119 486469 A7 B7 五、發明舞明（117 ) 1 ◦ %囀檬酸溶液間。再將有機萃取液乾燥（硫酸鎂）及 蒸發。而後藉於矽膠上進行急驟色層分離法（5 X2 0公 分柱，1 : 2乙酸乙酯/己烷爲洗提液）予以純化，即得 黃色固狀之標題化合物，2 . 36克，59%產率，熔點 1 2 3 - 1 2 5 °C 〇 B · CONHCH2CH2CH3 05 將已脫氣之第A部化合物（1 · 10克，5 · 47毫 莫耳）及3 3 0毫克1 0%鈀/碳之2 5毫升乙酸乙酯漿 液於室溫下，於氫氣層下攪拌1 6小時。而後令反應通過 寅氏鹽中過濾，再予蒸發，即得白色固狀之標題化合物， 89 4 毫克，81%，熔點· 61 — 63 °C。 C . 〇S!tBuMe2 ______ i 經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 於氬下，於0°C下，將10 · 5克（0 · 15莫耳） 咪唑及2 0 · 7克（0 · 1 4莫耳）特丁基二甲基甲矽烷 基氯先後加至49毫升（0 · 55莫耳）1，4 一 丁二醇 之2 5毫升二甲基甲醯胺溶液中。再將反應徐緩加溫至室 溫，並攪拌1 8小時，於此時將反應以乙醚稀釋及以氯化 銨，水，碳酸鈉，鹽水清洗並予乾燥（硫酸鎂）。所得無 色液態 ’50克，乃含有約15 %之二甲矽烷基化之化合物。 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 12〇 _ 486469 A7 ___ B7 五、發明説明（118) 於童下，於0 °C下，將7 · 3克（1 0 8毫莫耳）咪 唑及16 · 7克（64毫莫耳）三苯膦加至8 .5克（ 4 2毫莫耳）上示醇之5 0毫升四氫呋喃溶液中，再將此 混合物攪拌4 5分鐘（溶液變爲均勻），於此時將 16 · 2克（64毫莫耳）碘之50毫升四氫呋喃液於 2 0分鐘期間逐滴加入。繼而將反應攪拌丨小時，以己烷 稀釋，以1莫耳濃度亞硫酸氫鈉，碳酸鈉，鹽水清洗並予 乾燥（硫酸鈉）。再將所得餘留物以乙醚碾磨（3次）， 過濾（以移去三苯膦化氧）及蒸發，即得1 〇克（61 % )淡黃色油狀之標題碘丁烷。 (請先閲讀背面之注意事項再填寫本頁)2 '3 —dihydrol 1 1 [4 1 [4— (2,3 ~~ per Gan * ~ Huangyl-1 1-Hydroxy-1H-Iso-Earthyl-2-A) -1 1 Basic] Ding Printing of Employee Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs] -N—Bing 1 1 Η — 芘 1 1 甲 醯 __ 一 '—___ I CONHCH2CH2CH3〇ό— ~~ ^ —— at room temperature Under argon, add 15.0 ml of chloramidine solution (30. 0 mmol, 2 moles of dichloromethane), and then add 0.1 ml of dimethylformamide to the stirred solution. Of C〇2 卩 (―⑺ 丨 (3.20g'20.0mmol) in 20ml of Dichloromethane Academy Award solution. A light yellow solution can be obtained after the strong gas is released. 1 hour later, # & amp The mixture should be evaporated at a temperature of less than 25 ° C, and the residue was dissolved in 10 ml of tetrahydrofuran. Then at-10 ° C under argon, this solution was added dropwise over a period of 15 minutes. To 3.5 ml of n-propylamine (46 mmol) in 25 ml of tetrahydrofuran. After one hour, divide the reaction mixture in ethyl acetate and (please read the precautions on the back before filling this page). The scale is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm), Λ -119 486469 A7 B7 V. Inventive dance Ming (117) 1 ◦% citric acid solution. Then the organic extract is dried (sulfuric acid Magnesium) and evaporation. Then purified by flash chromatography (5 x 20 cm column, 1: 2 ethyl acetate / hexane as eluent) on silica gel to obtain the title compound as a yellow solid, 2 36 g, 59% yield, melting point 1 2 3-1 2 5 ° C 〇B · CONHCH2CH2CH3 05 The degassed Part A compound (1 · 10 g, 5. 47 mmol) and 3 3 0 25 milligrams of 10% palladium / carbon of 25 ml of ethyl acetate slurry was stirred at room temperature under a hydrogen layer for 16 hours. Then the reaction was filtered through Yin's salt and evaporated to obtain the title of a white solid. Compound, 89 4 mg, 81%, melting point · 61 — 63 ° C. C. 〇S! TBuMe2 ______ i Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page) at Under argon at 0 ° C, 10 · 5 g (0 · 15 mol) of imidazole and 2 · 7 g (0 · 1 4 mol) of tert-butyl di The methylsilyl chloride was added to 49 ml (0.55 mol) of 1,4-butanediol in 25 ml of dimethylformamide solution. The reaction was slowly warmed to room temperature and stirred for 1 minute. At 8 hours, the reaction was diluted with ether and washed with ammonium chloride, water, sodium carbonate, brine and dried (magnesium sulfate). The obtained colorless liquid was '50 g and contained about 15% of a dimethylsilylated compound. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 12〇_ 486469 A7 ___ B7 V. Description of the invention (118) Under the child, at 7 ° C, put 7 · 3 grams (1 0 8 millimoles) of imidazole and 16.7 grams (64 millimoles) of triphenylphosphine were added to a solution of 8.5 grams (42 millimoles) of the above-mentioned alcohol in 50 ml of tetrahydrofuran, and the mixture was stirred for 4 hours. 5 minutes (the solution became homogeneous), at which time 16.2 g (64 mmol) of iodine in 50 ml of tetrahydrofuran was added dropwise over a period of 20 minutes. The reaction was then stirred for 1 hour, diluted with hexane, washed with 1 mole sodium bisulfite, sodium carbonate, brine and dried (sodium sulfate). The resulting residue was triturated with ether (3 times), filtered (to remove triphenylphosphine oxide) and evaporated to give 10 g (61%) of the title iodobutane as a pale yellow oil. (Please read the notes on the back before filling this page)

經濟部中央標隼局員工消費合作杜印製 於一 5 °C下，於氬下，將正丁基鋰溶液（2 · 70毫 升’6.75毫莫耳，2· 5莫耳濃度之己烷液）加至已 攪拌之二異丙胺（0 · 95升，6 · 8毫莫耳）之10毫 升四氫呋喃溶液中，再攪拌1 5分鐘。而將第B部化合物 (59 3毫克，3 · 38毫莫耳）之5毫升四氫呋喃溶液 於1 0分鐘期間加入。再將所得深橘色溶液攪拌3 0分鐘 繼而將第C部1 一特丁基二甲基甲矽烷氧基一 4 一碘丁 烷（1 · 03克，3 . 31毫莫耳）之5毫升四氫呋喃溶 液加入。淡黃色溶液乃於1小時內形成。使用飽和碳酸氫 本紙張尺度適用中國國家標準（CNS ) A4規格( 210X297公釐）一 121 - 486469 A7 __B7 _ 五、發明説明（119) 鈉溶液冷反應混合物之反應中止，再以乙酸乙酯萃取兩次 。而後將有機萃取液結合，乾燥（硫酸鈉）及蒸發。而後 藉於矽膠上進行急驟色層分離法予以純化，即得無色油狀 之標題化合物（680毫克，58%)。Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs was printed at 5 ° C and under argon. A solution of n-butyllithium (2.70 ml '6.75 millimolar, 2.5 mole hexane in hexane ) Was added to a stirred solution of diisopropylamine (0.95 liters, 6.8 millimoles) in 10 ml of tetrahydrofuran and stirred for an additional 15 minutes. A solution of Part B compound (59 3 mg, 3.38 mmol) in 5 ml of tetrahydrofuran was added over 10 minutes. The resulting dark orange solution was stirred for 30 minutes, and then 5 ml of Part 1-1-butyldimethylsilyloxy-4-iodobutane (1.03 g, 3.31 mmol) was added. Tetrahydrofuran solution was added. A light yellow solution formed within 1 hour. Saturated bicarbonate paper This paper applies Chinese National Standard (CNS) A4 specification (210X297 mm) 121-486469 A7 __B7 _ V. Description of the invention (119) The reaction of the cold reaction mixture of sodium solution is stopped, and then extracted with ethyl acetate twice. The organic extracts were combined, dried (sodium sulfate) and evaporated. It was then purified by flash chromatography on silica gel to obtain the title compound (680 mg, 58%) as a colorless oil.

於室溫下，於氬下，將四丁銨化氟溶液（3毫升，3 莫耳，1莫耳濃度之四氫呋喃液）加至第D部化合物（ 675毫克，1·73毫莫耳）之5毫升四氫呋喃溶液中 。1小時後，令反應混合物分界於乙酸乙酯及1 〇%檸檬 酸溶液間。再將有機萃取液乾燥（硫酸鎂）及蒸發，而後 藉於矽膠上進行急驟色層分離法（2 . 5x15公分柱， 1 : 4己烷/乙酸乙酯）予以純化，即得無色油狀之標題 化合物（3 8 0毫克，8 0 % )。Add tetrabutylammonium fluoride solution (3 ml, 3 moles, 1 mole of tetrahydrofuran solution) to the compound in Part D (675 mg, 1.73 mmol) at room temperature under argon. 5 ml of tetrahydrofuran solution. After 1 hour, the reaction mixture was delimited between ethyl acetate and 10% citric acid solution. The organic extract was dried (magnesium sulfate) and evaporated, and then purified by flash chromatography (2.5 x 15 cm column, 1: 4 hexane / ethyl acetate) on silica gel to obtain a colorless oil. The title compound (380 mg, 80%).

經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 於氬下，於室溫下，先將三苯膦（3 6 5毫克， 1 · 39毫莫耳）及咪唑（210毫克，3 · 0毫莫耳） ，後將碘（360毫克，1 · 39毫莫耳）之5毫升四氫 呋喃液加至第E部化合物（380毫克，1 · 38毫莫耳 )之5毫升四氫呋喃溶液中。15分鐘後’使用5%亞硫 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-122 — " 486469 A7 B7 五、發明説明（12〇) 酸氫鈉溶液令反應中止，再以乙醚萃取。繼而將有機萃取 液乾燥（硫酸鎂）及蒸發。而後藉於矽膠上進行急驟色層 分離（5X1 5公分柱，5 : 7乙酸乙酯/己烷）而予以 純化，即得無色油狀之標題化合物（442毫克，83% )〇 G· 2，3 —二氫基一 1 一〔4-〔4 一（2，3 -二氫 基一 1 一合氧基一 1 Η -異朵一 2 -基）一 1 一呢B定基 ]丁基]一 N —丙基一 1 Η —芘一 1 一甲醯胺_ 經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 於室溫下，於氬下，將實例1第G部化合物（2 6 5 毫克，1 . 23毫莫耳）加至已攪拌之第F部化合物（ 430毫克，1·12毫莫耳）之5毫升二甲基甲醯胺溶 液中。再將反應加熱至50 °C，14小時後，使用10% 亞硫酸氫鈉溶液令反應中止，再以乙酸乙酯萃取。繼而將 有機萃取液乾燥（硫酸鎂），蒸發及由甲苯中再蒸發兩次 。而後藉於矽膠上進行急驟色層分離法（2 · 5x 1 5公 分之柱，1:9甲醇/乙酸乙酯）而予以純化，即得無色 無定形固狀之標題化合物（425毫克，88%)。 IR (薄膜）3470，2940，1680，1660 ，1530，1510，1470，1455，740 c m 一 1 〇 C 3〇H 39N 3〇 2 · 0 ·9 4Η2〇 之計算值： (：，73·45;Η，8·3 0;Ν，8·57 實測值：C，7 3 · 4 4 ; Η，8 · 1 1 : Ν，8 · 4 7 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）-123 - 486469 經濟部中央標隼局員工消費合作社印製 A7 _B7_ 五、發明説明（121 ) MS (電噴霧，+ 離子）m/e 474 (M+H) 1 H NMR(CDC13，300MHz) δ 7.83(d，lH，J=7.3Hz) 7 · 5 2 - 7 · 4 4 ( m，3 Η ) 7.3〇-7.23(m，4H) 5.53(t，lH，J = 5.5Hz) 4 · 3 5 ( s，2 H ) 4 · 3 0 ( 5 - plet， 1 H ， J = 5 · 3 H z ) 4.01(dd，lH，J = 7.2，7.8 Hz) 3 · 1 3 ( m，2 H ) 3.04(d，2H，J = 9.8Hz) 2 · 9 2 ( t，2 H，J = 6 · 7 H z ) 2 · 5 0 ( 5 - plet, 1 H ， J = 5 . 5 H z ) 2.38(t，4H，J=7.7Hz) 2.18 - 1.84(m，9H) 1.56 — 1.35(m，6H) 0.81 (t，3H，J=7.4Hz) ppm o 實例2 7 (請先閲讀背面之注意事項再填寫本頁) ·裝· 訂 本紙張又度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 486469 A7 B7 五、發明説明（122)Printed by the Employees' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling this page). Under argon, at room temperature, first triphenylphosphine (36.5 mg, 1.39 mmol) ) And imidazole (210 mg, 3.0 mmol), then 5 ml of tetrahydrofuran solution of iodine (360 mg, 1.39 mmol) was added to the compound of Part E (380 mg, 1.38 mmol) ) In 5 ml of tetrahydrofuran solution. After 15 minutes' use of 5% sulphur paper standard applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) -122 — & 486 469 A7 B7 V. Description of the invention (12) The sodium hydrogen acid solution stopped the reaction, Extract with ether. The organic extract was then dried (magnesium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (5 × 1 5 cm column, 5: 7 ethyl acetate / hexane) to obtain the title compound (442 mg, 83%). 3-dihydro-1, 1- [4- [4- (2,3-dihydro-1, 1-oxyl-1, 1-isobutyr-2-yl), 1-1, B-base] butyl] -1 N —propyl-1 Η — 芘 -1 1-methylamine _ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) At room temperature, under argon, place Example 1 Part G compound (265 mg, 1.23 mmol) was added to a stirred solution of Part F compound (430 mg, 1.12 mmol) in 5 ml of dimethylformamide . The reaction was heated to 50 ° C. After 14 hours, the reaction was stopped with a 10% sodium bisulfite solution and extracted with ethyl acetate. The organic extract was then dried (magnesium sulfate), evaporated and evaporated twice from toluene. It was then purified by flash chromatography on a silica gel (2.5 x 15 cm column, 1: 9 methanol / ethyl acetate) to obtain the title compound (425 mg, 88%) as a colorless amorphous solid. ). IR (thin film) 3470, 2940, 1680, 1660, 1530, 1510, 1470, 1455, 740 cm-Calculated value of 1 〇C 3〇H 39N 3〇2 · 0 · 9 4Η2〇: (:, 73 · 45; Η, 8 · 3 0; Ν, 8.57 Measured value: C, 7 3 · 4 4; Η, 8 · 1 1: Ν, 8 · 4 7 This paper size applies to China National Standard (CNS) Α4 specification (210X297 (Mm) -123-486469 Printed by A7 _B7_ of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (121) MS (Electrospray, + ion) m / e 474 (M + H) 1 H NMR 300MHz) δ 7.83 (d, lH, J = 7.3Hz) 7 · 5 2-7 · 4 4 (m, 3 Η) 7.3〇-7.23 (m, 4H) 5.53 (t, lH, J = 5.5Hz) 4 · 3 5 (s, 2 H) 4 · 3 0 (5-plet, 1 H, J = 5 · 3 H z) 4.01 (dd, lH, J = 7.2, 7.8 Hz) 3 · 1 3 (m, 2 H) 3.04 (d, 2H, J = 9.8 Hz) 2 · 9 2 (t, 2 H, J = 6 · 7 H z) 2 · 5 0 (5-plet, 1 H, J = 5. 5 H z ) 2.38 (t, 4H, J = 7.7Hz) 2.18-1.84 (m, 9H) 1.56 — 1.35 (m, 6H) 0.81 (t, 3H, J = 7.4Hz) ppm o Example 2 7 (Please read the (Please fill in this page again for precautions) Chinese National Standard (CNS) A4 size (210X297 mm) _ 486469 A7 B7 V. invention is described in (122)

1 一〔4 一〔4 一（2，3 -二氫基一 1 一合氧基一 1H 一異蚓P朵一 2 —基）一 1 一喊啶基〕丁基〕一 2 -苯基一 N —丙基一 1 Η —喆一 1 一甲醯胺_ Α. OSiPh2tBu (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作杜印製 於 15 . 化鈉（ 耳）之 沈澱物 苯基氯 理。再 〇 15 繼而將 膠上進 )而予 ，8 2 室溫下 3 6克 6 . 9 2 0 0 形成。 基矽烷 將反應 分鐘後 有機層 行急驟 以純化 % )。 ，於Μ ，0 · 7 5克 毫升四 而後將 (4 7 自生地 ，使用 結合， 色層分 ，即得 下，將 17 4 ，6 0 氫呋喃 漿液攪 .8 2 加溫至 水令反 乾燥（ 離法（ 無色油 Β.1 1 [4 1 [4 1 (2,3-dihydrol-1 1-oxyl 1H 1-isopropylammonium 2-methyl) 1 1 1-pyridyl] butyl] 2 -phenyl-1 N —propyl-1 Η — 喆 -1 1 methylamine _ Α. OSiPh2tBu (Please read the precautions on the back before filling out this page) The consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs is printed on 15. Sodium ( Ear) precipitates phenylchloride. 015 and then the glue is advanced), and 8 2 6 6.9 2 0 0 formed at room temperature. The silyl group was reacted after a minute to purify the organic layer to purify%). In M, 0.75 g ml of four and then (4 7 spontaneously, using a combination, color separation, that is, the 17 4, 60 0 hydrogen furan slurry was stirred. 8 2 Warm to water to make it dry (Leaving method (colorless oil B.

AcO 2 - 丁烯一 1，4 一二醇 莫耳） %礦油 漿液中 拌1 6 克，0 4 0 °C 應中止 硫酸鈉 1 2 X 狀之標 於2 0分鐘 分散液，0 。氯體乃釋 小時，繼而 • 1 7 4 莫 ，此時有清 ，再以己烷 )及蒸發。 3 0公分柱 題化合物（ 期間加至氫 • 1 7 4 莫 出且有稠厚 以特丁基二 耳）快速處 澈溶液形成 萃取兩次β 而後藉於矽 ，二氯甲烷 4 6 · 6 克 0SiPh2tBuAcO 2-butene-1,4-diol mol)% Mineral oil Mix 16 grams in the slurry, 0 4 0 ° C should be suspended sodium sulfate 1 2 X-shaped mark in 20 minutes dispersion, 0. Chlorine is released for an hour, then • 174 Mo, at which time it is cleared, and then hexane) and evaporated. 30 cm column title compound (added to hydrogen • 1 7 4 during the period and thick with tert-butyl di-ear) was quickly treated to form a clear solution and extracted twice β, then borrowed from silicon, 4 6 · 6 g 0SiPh2tBu

本紙張尺度適用中國國家標準（CNS -125 - 486469 A7 B7 五、發明説明（l23 ) 於室溫下，於氬下，將乙酸酐（2. 4毫升， 22 - 5毫莫耳）及4 一二甲胺基吡啶（20毫克， 0 · 16毫莫耳）加至已攪拌之第A部化合物（6 . 5 3 克，20 · 0毫莫耳）及三乙胺（3 · 53毫升， 25 · 3毫莫耳）之50毫升二氯甲烷溶液中。再將反應 於低於3 0°C之溫度下蒸發，而後令之分界於1 〇%檸檬 酸及己烷間。繼而將有機層以水及飽和碳酸氫鈉溶液清洗 ，並予乾燥（硫酸鈉）及蒸發。離析出之無色油狀物（ 7 · 02克，95%)乃用於第F部中而不必更進一步純 化。 c,This paper size applies the Chinese national standard (CNS -125-486469 A7 B7 V. Description of the invention (l23) At room temperature, under argon, acetic anhydride (2.4 ml, 22-5 millimoles) and 4 a Dimethylaminopyridine (20 mg, 0.16 mmol) was added to the stirred Part A compound (6.53 g, 20.0 mmol) and triethylamine (3.53 ml, 25 · 3 millimoles) in 50 ml of dichloromethane. The reaction was evaporated at a temperature below 30 ° C, and then the boundary was between 10% citric acid and hexane. Then the organic layer was separated by Water and saturated sodium bicarbonate solution were washed, dried (sodium sulfate) and evaporated. The isolated colorless oil (7.02 g, 95%) was used in Part F without further purification. C,

CCvQ (請先閱讀背面之注意事項再填寫本頁) 經 濟 部 中 標 隼 局 員 .工 消 費 合 作 社 印 製 將無水氯化鈽（16 . 00克，64 . 9毫莫耳）於 已於油浴中加熱至1 4 5°C之抽空燒瓶中攪拌2小時。而 後將燒瓶以氬氣溢流，冷卻至室溫，而後於冰浴中冷卻至 0°C，繼而將1 5 0毫升四氫呋喃加至此粉末中。將已攪 拌之漿液加溫至室溫。1 4小時後，將燒瓶再度冷卻至0 °C，繼而將苯基鎂化氯溶液（21 · 2毫升，63 · 6毫 莫耳，3莫耳濃度之乙醚液）加入。再將所得黃色漿液攪 拌1 · 5小時，而後將2 -芘滿酮（5 · 45克， 41 · 2毫莫耳，新近色層分離過）加入。30分鐘後’ 使用1 0 %檸檬酸令反應混合物之反應中止，並以乙醚萃 取兩次。繼而將有機萃取液乾燥（硫酸鎂）及蒸發。再藉 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 126 一 486469 A7 B7 五、發明説明（l24) 於矽膠士進行急驟色層分離法（5x20公分柱，17 : 3二氯甲烷/己烷）予以純化，即得無色油狀之標題化合 物（6 · 66 克，77%)。 將硫酸氫鉀（6 · 4克，.4 7毫莫耳）加至純第C部 化合物（6 · 40克，30 · 4毫莫耳）中。再將混合物 於氬下攪拌，而後置於已加熱至1 6 0°C之油浴中。將所 得固塊冷卻，令之分界於二氯甲烷及水間。繼而將有機層 乾燥（硫酸鎂）及蒸發，即得白色固狀之標題化合物（ 5 .84 克，100%)，熔點 164 — 164 °C。 (請先閱讀背面之注意事項再填寫本頁)CCvQ (Please read the notes on the back before filling out this page) Member of the Ministry of Economic Affairs won the bidding. Bureau of Industry and Consumer Cooperatives printed anhydrous thorium chloride (16.00 g, 64.9 mmol) in the oil bath Stir in an evacuated flask to 145 ° C for 2 hours. The flask was then flushed with argon, cooled to room temperature, and then cooled to 0 ° C in an ice bath, and 150 ml of tetrahydrofuran was added to the powder. Warm the stirred slurry to room temperature. After 14 hours, the flask was cooled again to 0 ° C, and then a phenylmagnesium chloride solution (21.2 ml, 63.6 mmol, 3 molar ether solution) was added. The resulting yellow slurry was stirred for an additional 1.5 hours, and then 2-permanone (5.54 g, 41.2 mmol, freshly separated layers) was added. After 30 minutes' the reaction of the reaction mixture was stopped with 10% citric acid and extracted twice with ether. The organic extract was then dried (magnesium sulfate) and evaporated. This paper size is also applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-126-486469 A7 B7 V. Description of the invention (l24) The rapid color separation method (5x20 cm column, 17: 32) Methyl chloride / hexane) was purified to obtain the title compound (6.66 g, 77%) as a colorless oil. Potassium hydrogen sulfate (6.4 g, .47 mmol) was added to the pure Part C compound (6.4 g, 30.4 mmol). The mixture was stirred under argon and placed in an oil bath heated to 160 ° C. The resulting solids were cooled and delimited between methylene chloride and water. The organic layer was then dried (magnesium sulfate) and evaporated to give the title compound (5.84 g, 100%) as a white solid with a melting point of 164-164 ° C. (Please read the notes on the back before filling this page)

經濟部中央標隼局員工消費合作社印裝 於0°C下，於氬下，將正丁基鋰（3 · 0毫升， 7 · 50毫莫耳，2 · 5莫耳濃度之己烷液）於10分鐘 期間加至第D部化合物（1 · 481克，7 · 70毫莫耳 )之2 0毫升四氫呋喃溶液中。再將所得深橘色溶液攪拌 1小時。而後使用數小片已以四氫呋喃清洗之乾冰以令反 應中止。繼而將所得稠厚黃色漿液攪拌1小時，而後以 2 0毫升2莫耳濃度氫氧化鉀溶液處理。再將此溶液以乙 醚萃取兩次’繼而使用3當量濃度硫酸以使水性餘留物之 p Η達2。再將混合物以乙酸乙酯萃取三次，將萃取液結 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐）_ 127 - 486469 A7 B7 五、發明説明（l25 ) 合’乾m (硫酸鎂）及蒸發，即得淡黃色粉狀之標題化合 物（1· 5 0 克，82%)，熔點 212 - 215 °C。The Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, printed at 0 ° C and argon, put n-butyllithium (3.0 ml, 7.50 millimoles, 2.5 moles of hexane) To a solution of Part D compound (1.481 g, 7.70 mmol) in 20 ml of tetrahydrofuran over a period of 10 minutes. The resulting dark orange solution was stirred for an additional hour. Several small pieces of dry ice washed with tetrahydrofuran were then used to stop the reaction. The resulting thick yellow slurry was then stirred for 1 hour and then treated with 20 ml of a 2 molar potassium hydroxide solution. This solution was then extracted twice with ether 'and then 3 equivalents of sulfuric acid were used to achieve a p of 2 for the aqueous residue. The mixture was extracted three times with ethyl acetate, and the paper size of the extract was applied to the Chinese National Standard (CNS) A4 (210 × 297 mm) _ 127-486469 A7 B7 V. Description of the invention (l25) combined with dry (sulfuric acid) Magnesium) and evaporation to give the title compound (1.50 g, 82%) as a pale yellow powder, melting at 212-215 ° C.

經濟部中央標隼局員工消費合作社印製 將第E部化合物（890毫克，3.77毫莫耳）， 第B部化合物（2 · 55克，3 · 77毫莫耳）及三苯膦 (190毫克，0 · 724毫莫耳）之混合物由甲苯中蒸 發兩次。令混合物溶於2 0毫升四氫呋喃中，於·下攪拌 ，再以雙（三甲基甲矽烷基）乙醯胺（BSA) (3 · 7 毫升，15毫莫耳）處理。30分鐘後，將肆（三苯膦） 鈀（0) (430毫克，0 · 39毫莫耳）加入，再將反 應設定至迴流。1 6小時後，將橘色溶液冷卻，蒸發及由 甲醇中再蒸發兩次。繼而令膠黏餘留物溶於乙醚中及以 1 0%檸檬酸清洗一次。再將有機萃取液乾燥（硫酸鎂） ，蒸發及由甲苯中再蒸發一次。 於氬下，於室溫下，先將草醯氯（0 . 9毫升， 7 · 0毫莫耳）後將二甲基甲醯胺（0 · 05毫升）加至 已攪拌之此產物之10毫升二氯甲烷溶液中。1小時後， 將反應蒸發以得橘色油狀物，再令之溶於1 0毫升四氫呋 喃中。 於0 °C下，將此溶液於1 0分鐘期間加至已攪拌之正 丙胺（1.4毫莫耳，16毫莫耳）之10毫升四氫呋喃 (請先閲讀背面之注意事項再填寫本頁) 、言Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, Compound E (890 mg, 3.77 mmol), Compound B (2.55 g, 3.77 mmol) and Triphenylphosphine (190 mg The mixture was evaporated twice from toluene. The mixture was dissolved in 20 ml of tetrahydrofuran, stirred at. And then treated with bis (trimethylsilyl) acetamide (BSA) (3.7 ml, 15 mmol). After 30 minutes, tris (triphenylphosphine) palladium (0) (430 mg, 0.39 mmol) was added and the reaction was set to reflux. After 16 hours, the orange solution was cooled, evaporated and evaporated twice more from methanol. The adhesive residue was then dissolved in ether and washed once with 10% citric acid. The organic extract was dried (magnesium sulfate), evaporated and evaporated again from toluene. Under argon at room temperature, add chlorpyrrolidine (0.9 mL, 7.0 mmol) and then add dimethylformamide (0.05 mL) to 10 of this product that has been stirred. Ml of dichloromethane solution. After 1 hour, the reaction was evaporated to give an orange oil, which was then dissolved in 10 ml of tetrahydrofuran. At 0 ° C, add this solution to the stirred n-propylamine (1.4 mmol, 16 mmol) in 10 ml of tetrahydrofuran over 10 minutes (please read the precautions on the back before filling this page), Speech

I 本紙張尺度逍用中國國家標準（CNS ) A4規格（210X297公釐）-128 486469 A7 __B7 五、發明説明（126) 溶液中％ 1小時後，將反應混合物以乙醚稀釋，及以1 〇 %檸檬酸清洗一次。繼而將有機萃取液乾燥（硫酸鎂）及 蒸發。再藉於矽膠上進行急驟色層分離法（5 X 2 0公分 柱’二氯甲烷）予以純化，即得橘色油狀之標題化合物（ 1 · 5 0 克，7 7 % )。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於氬下，於室溫下，將四丁銨化氟（10毫升，10 毫莫耳，1莫耳濃度之四氫呋喃液）加至已攪拌之第F部 化合物（2 · 15克，4 · 18毫莫耳）之15毫升四氫 呋喃溶液中。1小時後，使用鹽水令反應中止，再以乙酸 乙酯萃取三次。而後將有機萃取液乾燥（硫酸鎂）及蒸發 再藉於矽膠上進行急驟色層分離法（5 X 1 5公分柱， 3 : 2己烷/乙酸乙酯）予以純化，即得無色玻璃狀之標 題化合物（1·09克，75%)。I The paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) -128 486469 A7 __B7 5. Description of the invention (126)% in solution After 1 hour, the reaction mixture is diluted with ether and 10% Clean once with citric acid. The organic extract was then dried (magnesium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (5 x 20 cm column 'dichloromethane) to obtain the title compound (1.50 g, 77%) as an orange oil. (Please read the precautions on the back before filling this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed under argon, and tetrabutylammonium fluoride (10 ml, 10 mmol, 1 mole) was printed at room temperature. Concentration of tetrahydrofuran solution) was added to a stirred solution of Part F compound (2.15 g, 4.18 mmol) in 15 ml of tetrahydrofuran solution. After 1 hour, the reaction was quenched with brine and extracted three times with ethyl acetate. Then the organic extract was dried (magnesium sulfate) and evaporated, and then purified by flash chromatography (5 X 1 5 cm column, 3: 2 hexane / ethyl acetate) on silica gel to obtain a colorless glass. The title compound (1.09 g, 75%).

於室溫下，將5%鈀/碳（4 5毫克）加至已以氬淨 化之第G部化合物（20 9毫克’ 0 · 60毫莫耳）之 1 0毫升乙醇溶液中。再將燒瓶抽空’以氬氣淨化兩次及At room temperature, 5% palladium / carbon (45 mg) was added to a 10 ml ethanol solution of the Part G compound (209 mg'0.60 mmol) which had been purified with argon. The flask was evacuated ’and purged twice with argon and

本紙張尺度適用中國國家標準（CNS) A4規格（ 210X297公釐）-129乂 486469 Α7 Β7 五、發明説明（127) 以氣球冲之氫淨化，而後於氫氣層下攪拌3 〇分鐘。繼而 令反應通過寅氏鹽中過濾，再將濾液蒸發。而後藉急驟色 層分離法（2 . 5x1 5公分柱，1 : 1己烷/乙酸乙酯 )予以純化，即得白色泡沫狀之標題化合物（9 2毫克， 4 4%) 〇This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)-129 乂 486469 A7 B7 V. Description of the invention (127) Purify with a balloon of hydrogen and stir for 30 minutes under a hydrogen layer. The reaction was then filtered through Yin's salt and the filtrate was evaporated. Then purified by flash chromatography (2.5x1 5 cm column, 1: 1 hexane / ethyl acetate) to obtain the title compound (92 mg, 4 4%) as a white foam.

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 於室溫下，於氬下，將三苯膦（68毫克，0 . 26 毫莫耳）及咪唑（40毫克，0.57毫莫耳），而後將 碘（6 5毫克，0 · 26毫莫耳）之2毫升四氫呋喃加至 已攪拌之第Η部化合物（9 0毫克，0 · 2 6毫莫耳）之 2毫升四氫呋喃溶液中。1 〇分鐘後，使用1 〇%亞硫酸 氫鈉溶液令反應中止，再以乙醚萃取。而後將有機萃取液 乾燥（硫酸鎂）及蒸發。再藉於矽膠上進行急驟色層分離 法（2 · 5 X 1 5公分柱，二氯甲烷）予以純化，即得白 色固狀之標題化合物（87毫克，73%)，熔點125 一 1 2 7 °C。 J· 1 一〔4 一〔4 一（2，3 — 二氫基—1 一 合氧基 一 1 Η -異蚓p朵一 2 -基）一1 一哌啶基〕丁基〕一 2 - 苯基一 Ν —丙基一 1 Η_芘一 1 一甲醯胺____ 於室溫下，於氬下，將實例1第G部化合物（4 0毫 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X 297公釐） - 130 - 486469 A7 B7 經濟部中央標準局員工消費合作社印裝 五、發明説明（128) 克，σ' 181毫莫耳）加至已攪拌之第I部化合物（ 74毫克，0 · 1 6 1毫莫耳）之2毫升二甲基甲醯胺溶 液中。再將反應加熱至5 0 °C。1 4小時後，使用1 0 % 亞硫酸氫鈉溶液令反應中止，再以乙酸乙酯萃取。而後將 有機萃取液乾燥（硫酸鎂），蒸發及由甲苯中再蒸發兩次 。再藉於矽膠上進行急驟色層分離法（2。5x1 5公分 柱，1 : 12甲醇/乙酸乙酯）予以純化，即得白色固狀 之標題化合物（80毫克，91%)，熔點156 - 57 °C。 IR(KBr丸劑）3326，2942，2863， 1678，1622，1512，1454，1302, 737cm-1。 微量分析· C36H41N302· 1 · 1 7H20之計算值： C，76·02; Η，7·68;Ν，7.39 實測值：C，7 6 · 0 2 ; Η，7 · 4 3 ; Ν，7 · 3 0 ο MS (電噴霧，+ 離子）m/e 548 (M + H)。 1 H NMR(CDC13，300MHz) δ 7.83(d，lH，J=7.6Hz) 7.56(d，2H，J=7.6Hz) 7 · 4 0 ( s，1 Η ) 7·5 4-7·2(ιη，9Η) 5.3 2(t，lH，J=5.8Hz) 4.30(d，lH，J=7.3Hz) (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210x297公董）-131 - 486469 A7 B7 五、發明説明（129) ” 3 · 0 5 ( m，.2 Η ) 2 . 8 5 ( d，2 Η ) 2.62(dt，lH，J=4.2，9.2 Hz) 2-31 ( d t，1H，J=4.5，9.2 Hz) 2 · 0 6 ( m，2 H ) 1 . 9 4 ( m，2 H ) 1 · 7 1 ( m，4 H ) 1 · 2 6 ( m，4 H ) 〇.59(t，3H，J = 7.3Hz) 0 · 6 ( m，1 H ) 0.43(m，lH)ppm。 (請先閲讀背面之注意事項再填寫本頁) 衣· 訂 經濟部中央標隼局員工消費合作社印製 實例2 8(Please read the precautions on the back before filling out this page.) Printed at room temperature and under argon, Triphenylphosphine (68 mg, 0.26 mmol) and imidazole are printed at room temperature under the Consumer Cooperatives of the Central Bureau of Standards and Technology. (40 mg, 0.57 mmol), then 2 ml of tetrahydrofuran of iodine (65 mg, 0.26 mmol) was added to the agitated compound IX (90 mg, 0.26 mmol) ) In 2 ml of tetrahydrofuran solution. After 10 minutes, the reaction was stopped with 10% sodium bisulfite solution, and extracted with ether. The organic extract was then dried (magnesium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (2.5 x 1.5 cm column, dichloromethane) to obtain the title compound (87 mg, 73%) as a white solid with a melting point of 125 to 1 2 7 ° C. J · 1 a [4 a [4 a (2,3 —dihydrol — 1 —oxyl — 1 Η —isoammonium p — 2 —yl) — 1 —piperidinyl] butyl] — 2- Phenyl-N —propyl-1 1 Η_ 芘 -1 1-methylamine ____ At room temperature, under argon, the compound of Part G of Example 1 (40 millimeters of paper is applicable to Chinese National Standards (CNS) Α4 Specification (210 X 297 mm)-130-486469 A7 B7 Printed by the Consumers 'Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (128 g, σ' 181 millimoles) added to the agitated Part I compound (74 mg, 0.161 mmol) in 2 ml of dimethylformamide solution. The reaction was heated to 50 ° C. After 14 hours, the reaction was stopped with a 10% sodium bisulfite solution, and extracted with ethyl acetate. The organic extract was then dried (magnesium sulfate), evaporated and evaporated twice from toluene. It was then purified by flash chromatography (2.5x1 5 cm column, 1:12 methanol / ethyl acetate) on silica gel to obtain the title compound (80 mg, 91%) as a white solid, melting point 156- 57 ° C. IR (KBr pills) 3326, 2942, 2863, 1678, 1622, 1512, 1454, 1302, 737cm-1. Micro analysis · C36H41N302 · 1 · 1 Calculated value of 7H20: C, 76 · 02; Η, 7.68; N, 7.39 Found: C, 7 6 · 0 2; Η, 7 · 4 3; Ν, 7 · 3 0 ο MS (electrospray, + ion) m / e 548 (M + H). 1 H NMR (CDC13, 300MHz) δ 7.83 (d, 1H, J = 7.6Hz) 7.56 (d, 2H, J = 7.6Hz) 7 · 4 0 (s, 1 Η) 7 · 5 4-7 · 2 ( ιη, 9Η) 5.3 2 (t, lH, J = 5.8Hz) 4.30 (d, lH, J = 7.3Hz) (Please read the precautions on the back before filling this page) The paper size applies to the Chinese National Standard (CNS) A4 specifications (210x297 public directors) -131-486469 A7 B7 V. Description of the invention (129) ”3 · 0 5 (m, .2 Η) 2. 8 5 (d, 2 Η) 2.62 (dt, lH, J = 4.2, 9.2 Hz) 2-31 (dt, 1H, J = 4.5, 9.2 Hz) 2 · 0 6 (m, 2 H) 1. 9 4 (m, 2 H) 1 · 7 1 (m, 4 H) 1 · 2 6 (m, 4 H) 〇.59 (t, 3H, J = 7.3Hz) 0 · 6 (m, 1 H) 0.43 (m, lH) ppm. (Please read the notes on the back before filling (This page) Examples of clothing, print and print by the Central Consumers' Bureau of the Ministry of Economic Affairs, Consumer Cooperatives 2 8

反式一 2，3 —二氫基一 1 一〔4——〔4 一（2，3 —二 氫基一 1 一合氧基一 1H -異蚓P朵一 2 -基）一 1 一哌啶 基〕丁基〕一 2 —苯基一 N —丙基一 1 Η — 15 - 1 一甲醯 m_ ___ 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 132 486469 A7 B7 五、發明説明（130)Trans-2,3-dihydrol-1 1 [4 —— [4 a Pyridyl] butyl] -2 -phenyl -N -propyl -1 Η — 15-1 -methyl 醯 m_ ___ This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 132 486469 A7 B7 V. Invention Description (130)

經濟部中央標隼局員工消費合作社印製 於室溫下，將2克（32毫莫耳）甲酸銨加至682 毫克（1 · 3 4毫莫耳）實例2 7第F部化合物之1 0毫 升乙醇溶液中。再將漿液攪拌及以氮淨化2 0分鐘。將 1 0%鈀/碳（1克）加入後，將反應於氬下攪拌1 6小 時。而後將反應混合物通過Cel ite®中過濾，以乙酸乙酯 清洗β再將濾液以水清洗兩次及以鹽水清洗一次’繼而乾 燥（硫酸鎂）及蒸發。再藉於矽膠上進行急驟色層分離（ 5 x 1 5公分柱，1 : 9 9乙醚/二氯甲烷）予以純化， 即得無色油狀之標題化合物（35 4毫克，52%)。Β.Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, at room temperature, add 2 grams (32 millimoles) of ammonium formate to 682 milligrams (1.34 millimoles). Ml of ethanol solution. The slurry was stirred and purged with nitrogen for 20 minutes. After 10% palladium / carbon (1 g) was added, the reaction was stirred under argon for 16 hours. The reaction mixture was then filtered through Celite®, the β was washed with ethyl acetate, the filtrate was washed twice with water and once with brine 'followed by drying (magnesium sulfate) and evaporation. It was then purified by flash chromatography on a silica gel (5 x 1 5 cm column, 1: 99 ether / dichloromethane) to obtain the title compound (35 4 mg, 52%) as a colorless oil. Β.

於室溫下，於氬下，將四丁銨化氟（1 · 0毫升， 1·0毫莫耳，1莫耳濃度之四氫呋喃液）加至已攪拌之 第Α部化合物（3 15毫克，0 · 5 34毫莫耳）之3毫 升四氫呋喃溶液中。1小時後，使用鹽水令反應中止，再 以乙酸乙酯萃取三次。而後將有機萃取液乾燥（硫酸鎂） 及蒸發。再藉急驟色層分離法（2 · 5x1 5公分柱，3 :5己烷/乙酸乙酯）予以純北，即得白色泡沫狀之標題 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公嫠）_ 13 (請先閱讀背面之注意事項再填寫本頁) 486469 A7 _____B7五、發明説明（131 ) 化合物八1 3 5毫克，7 2 % )。At room temperature, under argon, tetrabutylammonium fluoride (1.0 ml, 1.0 millimolar, 1 mole tetrahydrofuran solution) was added to the stirred part A compound (3 15 mg, 0.534 mol) in 3 ml of tetrahydrofuran solution. After 1 hour, the reaction was quenched with brine and extracted three times with ethyl acetate. The organic extract was then dried (magnesium sulfate) and evaporated. Then use the rapid color layer separation method (2 · 5x1 5 cm column, 3: 5 hexane / ethyl acetate) to pure North, to obtain a white foam-like title. Public note) _ 13 (Please read the notes on the back before filling out this page) 486469 A7 _____B7 V. Description of the invention (131) Compound 135 mg, 72%).

經濟部中央標隼局員工消費合作社印製 毫莫耳）及咪唑（60毫克，〇·8 6毫莫耳），而後將 碘（92毫克，0 · 36毫莫耳）之1毫升四氫呋喃加至 已攪拌之第B部化合物（127毫克，0 · 361毫莫耳 )之2毫升四氫呋喃溶液中。1 5分鐘後，使用5%亞硫 酸氫鈉溶液以令反應中止，再以乙醚萃取。繼而將有機萃 取液乾燥（硫酸鎂）及蒸發。再藉急驟色層分離法（ 2·5x15公分柱，二氯甲烷）予以純化，即得無色玻 璃狀之標題化合物（101毫克，61%)。 D· 反式一 2，3 —二氫基一 1 一〔4一〔 4 — (2， 3 -二氫基一 1 一合氧基一 1H -異蚓跺一 2 -基）一 1 哌啶基〕丁基〕一 2 -苯基一 N -丙基一 1 Η - - 1 一 甲醯胺________ 於室溫下，於氬下，將實例1第G部化合物（5 4毫 克，0 · 244毫莫耳）加至已攪拌之第C部化合物（ 100毫克，0 · 217毫莫耳）之3毫升二甲基甲醯胺 溶液中。再將反應加熱至50 °C，14小時後，使用10 %亞硫酸氫鈉溶液以令反應中止，再以乙酸乙酯萃取。繼 而將有機萃取液乾燥（硫酸鎂），蒸發及由甲苯中再蒸發 本紙張尺度適用中國國家標準（〇~5)八4規格（2〖0父297公釐）_134^ (請先閱讀背面之注意事項再填寫本頁) 486469The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed millimoles) and imidazole (60 mg, 0.86 millimoles), and then added 1 ml of tetrahydrofuran to iodine (92 mg, 0.36 millimoles) to A solution of the compound of Part B (127 mg, 0.361 mmol) in 2 ml of tetrahydrofuran was stirred. After 15 minutes, a 5% sodium hydrogen sulfite solution was used to stop the reaction, followed by extraction with ether. The organic extract was then dried (magnesium sulfate) and evaporated. Purification by flash chromatography (2.5 x 15 cm column, dichloromethane) gave the title compound (101 mg, 61%) as a colorless glass. D · trans-1,2,3-dihydrol-1 1 [4— [4 — (2, 3 -dihydrol-1 1-oxyl- 1H-isoearmidine-2 -yl)-1 piperidine Group] butyl]-2-phenyl-N-propyl- 1 Η--1 monomethylamine ________ at room temperature under argon, the compound of Part G of Example 1 (54 mg, 0 · 244 mmol) was added to a stirred solution of Part C compound (100 mg, 0.217 mmol) in 3 ml of dimethylformamide. The reaction was heated to 50 ° C. After 14 hours, a 10% sodium bisulfite solution was used to stop the reaction, and then extracted with ethyl acetate. Then the organic extract is dried (magnesium sulfate), evaporated and re-evaporated from toluene. The paper size is applicable to the Chinese national standard (0 ~ 5) 8 4 specifications (2 〖0 parent 297 mm) _134 ^ (Please read the first (Please fill out this page again) 486469

經濟部中央標隼局員工消費合作社印製 A7 B7五、發明説明（132 ) 兩次。1而後藉於矽膠上進行急驟色層分離法（2· 5X 1 5公分柱，1 : 9己烷/乙酸乙酯）予以純化，即得淡 黃色無定形玻璃狀之標題化合物（105毫克，88%) 〇 IR (KBr 丸劑）3432，2 934，2 872， 1676，1516，1470，1 4 54，766， 7 3 7 c m -1 ° 微量分析· C36H43N30 2· 1 · 54H20之計算值： (：，74·87;Η，8·04;Ν，7·64 實測值：C，7 4 · 8 8 ; Η，7 · 8 2 ; Ν，7 · 3 3 〇 MS (電噴霧，+ 離子）m/e 550 · 5 (M+H) 〇 1 H NMR(CDC13，300MHz) δ 7.82(d，lH，J = 7.3Hz) 7.51 — 7. 14(m，12H) 5.66(t，lH，J = 5.2Hz) 4 · 3 3 ( m，2 H ) 4.26(dd，lH，J=0.7，3.6 Hz) 4.01(dd，lH，J=7.2，7.8 Hz) 3 · 2 8 ( m，4 H ) 2.95(d，2H，J = l〇.7Hz) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）- 135 一 (請先閲讀背面之注意事項再填寫本頁) i裝· 訂 486469 B7 明説. 明發五 4 2 0 3 8 2 18 5 8 mPrinted by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Invention Description (132) Twice. 1 Then purified by flash chromatography on a silica gel (2.5 × 15 cm column, 1: 9 hexane / ethyl acetate) to obtain the title compound (105 mg, 88 %) 〇IR (KBr pills) 3432, 2 934, 2 872, 1676, 1516, 1470, 1 4 54, 766, 7 3 7 cm -1 ° Micro analysis · C36H43N30 2 · 1 · 54H20 Calculated value: (: , 74 · 87; Η, 8.04; Ν, 7.64 Measured value: C, 7 4 · 8 8; Η, 7 · 8 2; Ν, 7 · 3 3 〇MS (electrospray, + ion) m / e 550 · 5 (M + H) 〇1 H NMR (CDC13, 300MHz) δ 7.82 (d, lH, J = 7.3Hz) 7.51 — 7. 14 (m, 12H) 5.66 (t, lH, J = 5.2 Hz) 4 · 3 3 (m, 2 H) 4.26 (dd, lH, J = 0.7, 3.6 Hz) 4.01 (dd, lH, J = 7.2, 7.8 Hz) 3 · 2 8 (m, 4 H) 2.95 ( d, 2H, J = l0.7 Hz) This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm)-135 I (Please read the precautions on the back before filling this page) Ming Fa. Ming Fa Wu 4 2 0 3 8 2 18 5 8 m

m 1 ( I J m J \]κ , XI/ r\ ， Η Η H 6 H 2 2 4 1 3 Z Η 1 Η 7m 1 (I J m J \] κ, XI / r \, Η Η H 6 H 2 2 4 1 3 Z Η 1 Η 7

m p p z H 明 說 構 。 結認 列確 下中 藉表 乃之 物後 合之 化構 它結 其一 之每 內於 圍 則 範基 明代 發取 本之 於例 落實 1 每 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-136 一 486469 A7 B7 五、發明説明（l34) 賨例m p p z H is clearly structured. Recognize and confirm that the debit table is the combination of the later and the other. It is included in the rules and regulations. Fan Jiming issued a copy of the case and implemented it in each case. (Please read the precautions on the back before filling out this page.) Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, the paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm)-136 486469 A7 B7 V. Description of Invention (l34) Example

其中Rlx爲Where Rlx is

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經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Η Η Η Η Η Η Η F Η Η Η Η Η OCH3 Η Η Η F CP3 Η Η C1 Η Η Η C1 Η Η Η Η Η Η 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 一 486469 A7 B7 五、發明説明（l35 ) 表A (績） 經濟部中央標準局員工消費合作社印製 R· Rb Rc Rd Η Η Cl Η Η Η Η 》~〇c丨 Η Η Η Η Η Η Η Cl Η Η ch3 Η Η CH3 Η sch3 Η Η Η Η Η och3 Η Η Η Η SCHa Η Η Η Η Η Η Η ^-ch2-=-h Η Η Η Η Η Η ^CH2-<1 (請先閲讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 ι38 一 486469 A7 B7 五、發明説明（l36)Η Η Η Η Η Η Η Η Η Η Η Η CH OCH3 Η Η Η F CP3 Η Η C1 Η Η Η C1 Η Η Η Η Η Η This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)- One 486469 A7 B7 V. Description of Invention (l35) Table A (Performance) Printed by R · Rb Rc Rd of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Η Η Cl Η Η Η Η ~ ～ Η Η Η Η Η Η Η Cl Η Η ch3 Η Η CH3 Η sch3 Note on the back, please fill in this page again) The size of the paper used for this edition applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)-ι38-486469 A7 B7 5. Description of the invention (l36)

表BTable B

Ru 其中Rlx爲表A中之（a )，（ b )或（c ) Q之實例Ru where Rlx is an example of (a), (b) or (c) Q in Table A

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

Cl οCl ο

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了$ Ο .環己基ο ο0rV άΥ α$ Ο .cyclohexyl ο ο0rV άΥ α

ο οCrsOVο οCrsOV

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〇 N〇 N

CH3 α>ν 处广 (請先閲讀背面之注意事項再填寫本頁) 裝.CH3 α > ν Chu Hiro (Please read the precautions on the back before filling this page).

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Ο Λ, 訂 F3C、 .CF3Ο Λ, order F3C, .CF3

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表CTable C

供表C用之X=H或F (請先閲讀背面之注意事項再填寫本頁)X = H or F for Form C (Please read the notes on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ _This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ _

A7 B7 五、發明説明（I39 )A7 B7 V. Description of the Invention (I39)

表DTable D

〇〇

0= XsH^ F 或0 = XsH ^ F or

0 Η R之實例0 Η R Examples

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cn ou, Ou, M.〇0^ (>〇iEtX)u》U卜 o (請先閲讀背面之注意事項再填寫本頁) 【裝. 訂 -1¾ 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X 297公釐）一 142 - 486469 A7 B7 五、發明説明（l4〇 )cn ou, Ou, M.〇0 ^ (> 〇iEtX) u》 U 卜 o (Please read the notes on the back before filling out this page) [Binding. Order-1¾ This paper size applies to Chinese National Standards (CNS) A4 specifications (210X 297mm)-142-486469 A7 B7 5. Description of the invention (l40)

表 ETable E

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經濟部中央標隼局員工消費合作社印製Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

w o oCr^ f 令 CCU〔:Vw o oCr ^ f Let CCU 〔: V

CrV c：^ 0r^ ^CrV c: ^ 0r ^ ^

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X 297公釐）__ 143 一 訂 486469 A7 B7 五、發明説明（Ml ) 表E (縳） α0 α σ〜 0r°> 〇τ〇% ότ。、 Η α〇Η α。 Cr\ 〇r«% ότΥ 〇Τ2η3 ΡΗ, CrfThis paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) __ 143 One order 486469 A7 B7 V. Description of the invention (Ml) Table E (bound) α0 α σ ~ 0r ° > 〇τ〇% ότ . , Η α〇Ηα. Cr \ 〇r «% ότΥ 〇Τ2η3 ΡΗ, Crf

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、1T 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）144 486469 A7 B7 五、發明説明（142) X-、 1T Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) 144 486469 A7 B7 V. Description of the invention (142) X-

• Z 表 F =3芴基型化合物 x ο a.• Z Table F = 3 芴 -based compounds x ο a.

Η ο ο 或认或Μν I R=丙基或 CF3CH2Η ο ο OR Μν I R = propyl or CF3CH2

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本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-145 — 486469 A7 B7 五、發明説明（I43 ) ii；基型化合物This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -145 — 486469 A7 B7 V. Description of the invention (I43) ii; Basic compounds

X 〇 0 〇 ο R·X 〇 0 〇 ο R ·

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本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-146 - 訂 486469 A7 B7 五、發明説明（l44 ) 表G (艚） li；基型環：Z =This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -146-486469 A7 B7 V. Description of the invention (l44) Table G (艚) li; Basic ring: Z =

經濟部中央標隼局員工消費合作社印製Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）__ 147 (請先閲讀背面之注意事項再填寫本頁) .•裝. 訂 486469 A7 B7 五、發明説明（i45) 表Η Ο II R-S- II 0This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) __ 147 (Please read the precautions on the back before filling out this page). • Packing. Order 486469 A7 B7 V. Description of Invention (i45) Table Η Ο II RS- II 0

X X爲Η或F X R之實例 (請先閱讀背面之注意事項再填寫本頁) •裝·X X is an example of Η or F X R (Please read the notes on the back before filling this page) • Installation ·

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訂 丫 .破 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-ΐ48 _ 486469 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（146) 說明本發明式I及Π化合物之先前表中，亦即包括4 -經取代哌啶異構體之化合物中，式I及Π化合物當然可 被本發明式I i及Π i化合物所取代，亦即化合物包括3 -經取代哌啶異構體。 賨例2 9 順式一 9 一〔4 一〔4 一（2，3 - 二氫基一 1H — 異口别 P朵一 2 —基）一 1 —哌_基〕丁基〕一 n 一丙基.一 9 H-荀一 9 一甲酿胺，N —氣 < 匕物____ .於〇°C下，於氬下，將3 —氯基過苯甲酸（約5 0% )(341毫克，0.99毫莫耳）之二氯甲烷（1毫升 )漿液逐滴加至實例1化合物（5 2 4毫克，0 · 9 9毫 莫耳）之二氯甲烷（1毫升）漿液中。再將反應於〇°C下 攪拌2 0分鐘，以二氯甲烷（1 5毫升）稀釋，以飽和碳 酸氫鈉（5毫升）及鹽水（5毫升）清洗，繼而於硫酸鎂 上乾燥。蒸發後可得6 1 2毫克白色泡沬狀物，將之藉於 矽膠（7 5克）上進行急驟色層分離並以.4 %至5%至7 %至1 0%甲醇/二氯甲烷階梯洗提而予以純化，即得白 色泡沬狀之乙酸乙酯（3 0 8毫克，58%)。 MS (ES) : 538〔M + H〕 分析· C34H39N303· 1 · 5H2〇之計算值： C，72.29;H，7.50;N，7.44 實測值：C，72.32;H，7.28;N，7.41 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-149 - 486469 A7 B7Ordering paper. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)-ΐ 48 _ 486469 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In the previous table of Π compounds, that is, compounds that include 4-substituted piperidine isomers, the compounds of formulae I and Π may of course be substituted by the compounds of formulae I i and Π i according to the invention, that is, the compounds Substituted piperidine isomers.賨 例 2 9 cis-1 9 1 [4 1 [4 1 (2,3-dihydrol 1H — isopropion P 2 —yl) — 1 —piperidyl] butyl] 1 n 1 propyl A 9H-H9-9 Methylamine, N-gas < Dagger ____. At 0 ° C, under argon, 3-chloroperbenzoic acid (about 50%) (341 A milligram, 0.99 millimolar) of dichloromethane (1 mL) slurry was added dropwise to a compound of Example 1 (542 mg, 0.99 millimoles) in a dichloromethane (1 mL) slurry. The reaction was stirred at 0 ° C for 20 minutes, diluted with dichloromethane (15 ml), washed with saturated sodium bicarbonate (5 ml) and brine (5 ml), and then dried over magnesium sulfate. After evaporation, 6 1 2 mg of white foam can be obtained, which is separated on a silica gel (75 g) for rapid color separation and separated from .4% to 5% to 7% to 10% methanol / dichloromethane. Stepwise elution and purification provided ethyl acetate (308 mg, 58%) as a white foam. MS (ES): 538 〔M + H〕 Analysis Calculated for C34H39N303 · 1 · 5H2〇: C, 72.29; H, 7.50; N, 7.44 Found: C, 72.32; H, 7.28; N, 7.41 (Please (Please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) -149-486469 A7 B7

五、發明説明（ ιπ) 實例3 η 2 -〔 1 一〔4 一〔9一（ 丁磺醯）一 9Η -芴—9 一基 〕丁基〕一 4 一哌啶基〕一 2，3 -二氫基一 1Η -異口引 口朵一 1 一酮_；_________Α. IV. Description of the invention (ιπ) Example 3 η 2-[1-[4-[9-(butanesulfonyl)-9--fluorene-9 -yl] butyl]-4-piperidinyl]-2, 3- Dihydrol-1Η-heterologous introduction of a flower 1 -one ketone _; _________ Α. I

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 於一 2 0°C下，將9 一羥基一（9Η) —芴（ 1 · 58克，10 · 0毫莫耳）及丁烷硫赶（〇 · 72克 ，8 · 0 0毫莫耳）之1 0毫升二氯甲烷溶液以三氟化硼 醚酸酯（1 · 28克，9 · 00毫莫耳）處理。再將反應 於一 20 °C下攪拌1小時，而後加溫至室溫。攪拌1 8小 時後，將燒瓶之內容物藉於矽膠（1 0 0克）上進行柱色 層分離並以已烷而後1 : 9二氯甲烷/己院洗提而予以純 化，即得1 . 5 4克（7 5 % )無色油狀之標題化合物。 薄層色層分離矽膠（1 : 9二氯甲烷/己烷） R f = 0 · 5 〇(Please read the precautions on the back before filling out this page) The Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, printed at -20 ° C, the 9-hydroxy-1 (9Η) — 芴 (1 · 58 grams, 10 · 0 mmol) and butane thiosulfate (0.72 g, 8.00 mmol) in 10 ml of dichloromethane solution with boron trifluoride etherate (1.28 g, 9.00 mmol) Moore) processing. The reaction was stirred at -20 ° C for 1 hour, and then warmed to room temperature. After stirring for 18 hours, the contents of the flask were purified by column chromatography on silica gel (100 g) and purified with hexane and then 1: 9 dichloromethane / hexane. 54 g (75%) of the title compound as a colorless oil. Thin layer chromatographic silica gel (1: 9 dichloromethane / hexane) R f = 0 · 5 〇

於一 78°C下，將第A部化合物（1 ·〇克， 本紙張尺度適用中國國家標準（CNS)A4規格（21〇X：297公釐）—MO - 486469At a temperature of 78 ° C, the compound of Part A (1.0 g, the size of this paper applies the Chinese National Standard (CNS) A4 specification (21 ×: 297 mm)-MO-486469

經濟部中央標準局員工消費合作社印製 A7 ______B7_五、發明説明（l48) 3 · 9~3毫莫耳）之1 0毫升四氫呋喃溶液以正丁基鋰之 己烷液（1 · 75毫升，4 · 40毫莫耳）及1 一氯基一 4 一溴基一丁烷（0 · 81克，4 · 70毫莫耳）先後處 理。再將反應攪拌0 · 5小時，而後加溫至室溫18小時 ，繼而將燒瓶之內容物以3 0毫升水性氯化銨溶液及3 0 毫升乙酸乙酯稀釋。再將有機部分乾燥（硫酸鈉）及濃縮 。而後將餘留物藉於矽膠（5 0克）上進行柱色層分離並 以2 : 98乙腈/二氯甲烷（500毫升）及15 : 85 二氯甲烷/己烷先後洗提而予以純化，即得1 · 0 0克（ 73%)無色油狀之標題化合物。 薄層色層分離矽膠（2 : 8二氯甲烷/己烷） R、= 0 · 4 〇 MS (ES，+ 離子）m/e 255 (M-SC4H9) ο C. (請先閲讀背面之注意事項再填寫本頁)Printed by A7 ____B7_ of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the Invention (l48) 3 · 9 ~ 3 millimoles in 10 ml of tetrahydrofuran solution with n-butyllithium in hexane (1.75 ml, 4 · 40 mmol) and 1-chloro-4,4-bromo-butane (0.81 g, 4.70 mmol) were processed successively. The reaction was stirred for another 0.5 hours, and then warmed to room temperature for 18 hours. The contents of the flask were then diluted with 30 ml of aqueous ammonium chloride solution and 30 ml of ethyl acetate. The organic portion was dried (sodium sulfate) and concentrated. Then the residue was purified by column chromatography on silica gel (50 g) and purified with 2: 98 acetonitrile / dichloromethane (500 ml) and 15: 85 dichloromethane / hexane. This gave 1.00 g (73%) of the title compound as a colorless oil. Thin layer color separation silica gel (2: 8 methylene chloride / hexane) R, = 0 · 4 〇MS (ES, + ion) m / e 255 (M-SC4H9) ο C. (Please read the note on the back first (Fill in this page again)

於0°C下，將3 —氯基過苯甲酸（m - CPBA)( 0 . 37克，80重量·172毫莫耳）一次地加 至第Β部化合物（0 · 30克，0 · 86毫莫耳）之二氯 甲烷（5毫升）溶液中。當以〇 . 1莫耳濃度碳酸鉀（ 2 0毫升）及乙醚（3 0毫升）稀釋時’將混合物攪拌一 小時。而後將有機部分予以乾燥（硫酸鈉）及濃縮。再將 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）一 151 一 486469 Α7 Β7 五、發明説明Ο49) 餘留物藉於矽膠（50克）上進行柱色層分離並以15 : 85乙酸乙酯/己烷洗提而予以純化，即得〇 · 24克（ 7 5%)無色油狀之標題化合物。 薄層色層分離矽膠（2 : 8二氯甲烷/己烷） R f = 0 · 0 7 〇 D. ' · . ;r.At 0 ° C, 3-chloroperbenzoic acid (m-CPBA) (0.37 g, 80 weight · 172 mmol) was added to the compound of Part B (0. 30 g, 0. 86) in one portion. MM) in dichloromethane (5 ml). When diluted with 0.1 mol potassium carbonate (20 ml) and diethyl ether (30 ml), the mixture was stirred for one hour. The organic portion was then dried (sodium sulfate) and concentrated. Then apply this paper size to Chinese National Standard (CNS) A4 specification (210X297 mm)-151-486469 A7 B7 V. Description of the invention 〇49) Residues are separated by silica gel (50 g) for column chromatography and separated by 15 : 85 ethyl acetate / hexane was eluted and purified to obtain 0.24 g (7 5%) of the title compound as a colorless oil. Thin layer chromatographic silica gel (2: 8 dichloromethane / hexane) R f = 0 · 0.7 〇 D. '·.; R.

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於室溫下，將碘化鈉（1 · 00克，6 · 66毫莫耳 )—次地加至第C部化合物（〇 · 24克，0 . 64毫莫 耳）之2 —丁酮（1 0毫升）溶液中。當以水（2 0毫升 )及乙醚（3 0毫升）稀‘釋之時，將混合物迴流3 0小時 。而後將有機部分予以乾燥（硫酸鈉）及濃縮。再於餘留 物藉於矽膠（50克）上進行柱色層分離並以15 : 85 乙酸乙酯/己烷洗提而予以純化，即得〇 · 24克（81 %)無色油狀之標題化合物。 E· 2 -〔1 一〔4 一〔9一（ 丁礦酿）一 9H -苟一 9 一基〕丁基〕一 4 一哌啶基〕一2，3 -二氫基-1H 一異吲 - 1 一酮____ 於室溫下，將0 · 38克（1 · 80毫莫耳）實例1 第G部化合物加至已攪拌之〇 · 7 0克（1 · 4 9毫莫耳 )第D部化合物之6毫升二甲基甲醯胺溶液中。再將反應 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 152 - 486469 Α7 Β7 經濟部中央標隼局員工消費合作社印製 五、發明説明（150) 混合物加溫至5 5 °C，而後令之攪拌2 4小時。繼而將混 合物以碳酸氫鈉溶液（5 0毫升）及乙酸乙酯（5 0毫升 )稀釋。再將諸層分離，將有機相乾燥（硫酸鈉）及濃縮 。而後將餘留物藉於矽膠（1 0 0克）上進行急驟柱色層 分離並以5:95甲醇/二氯甲烷（700毫升），繼而 5 : 95 : 0 · 5甲醇/二氯甲烷/氨（1升）洗提而予 以純化。再收集純溶離份並予濃縮，即得0 . 70克（ 8 5%)稠厚油狀之標題化合物，其於靜置後固化。 熔點.1 3 0 - 1 3 2 °C。 薄層色層分離矽膠（5 :95:1) 甲醇/二氯甲烷/氨）Rf = 〇 · 35。 分析· C34H4〇N2S〇3+〇 · 5H20 之計算值： C，72.79;H，7.30;N，4.96 ;S，5 · 6 8 實測值：C，7 2 · 2 5 ; Η，7 · 1 5 ; N，5 · 0 0 ;S，5 : 6 9 〇 實例3 1 9 一〔4一〔4 一〔 （1 ，1 一二甲基乙氧基）羰基〕胺 基〕一 1 一哌啶基〕丁基〕一2，7-二氟基一 Ν —（2 ，2 ，2 —三氟乙基）一 9Η —芴一 9 一甲醯胺__ (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐〉-153 一 486469 Α7 Β7 五、發明説明（Ιδί) 1'- Α·(Please read the notes on the back before filling out this page) Printed at room temperature by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, add sodium iodide (1.00 g, 6.66 mmol) to the Part C compound (0.24 g, 0.64 mmol) in 2-butanone (10 ml). When diluted with water (20 ml) and diethyl ether (30 ml), the mixture was refluxed for 30 hours. The organic portion was then dried (sodium sulfate) and concentrated. The residue was purified by column chromatography on silica gel (50 g) and purified with 15:85 ethyl acetate / hexane to obtain 0.24 g (81%) of the title as a colorless oil. Compound. E · 2-[1-[4-[9- (Butanite) -9H-Go-9-9-yl] butyl] -4-piperidinyl] -2,3-dihydro-1H-iso-indole -1 Monoketone ____ Add 0.38 g (1.80 mmol) of the compound from Part 1 of Example 1 to 0.70 g (1.49 mmol) of the compound at room temperature. Part D compound in 6 ml of dimethylformamide solution. Then the paper size of the paper is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 152-486469 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs 5. Description of the invention (150) The mixture is heated to 5 5 ° C, and then allowed to stir for 24 hours. The mixture was then diluted with sodium bicarbonate solution (50 ml) and ethyl acetate (50 ml). The layers were separated and the organic phase was dried (sodium sulfate) and concentrated. The residue was then subjected to flash column chromatography on silica gel (100 g) and separated with 5:95 methanol / dichloromethane (700 ml), followed by 5: 95: 0.5 methanol / dichloromethane / Ammonia (1 liter) was eluted and purified. The pure soluble fractions were collected and concentrated to give 0.70 g (85%) of the title compound as a thick oil, which solidified after standing. Melting point. 1 3 0-1 3 2 ° C. Thin layer chromatographic silica gel (5: 95: 1) methanol / dichloromethane / ammonia) Rf = 0.35. Analysis Calculated value of C34H4〇N2S〇3 + 〇. 5H20: C, 72.79; H, 7.30; N, 4.96; S, 5 · 6 8 Found: C, 7 2 · 2 5; Η, 7 · 1 5 N, 5 · 0 0; S, 5: 6 9 〇 Example 3 1 9-[4-[4-[(1,1-dimethylethoxy) carbonyl] amine]-1-piperidinyl 】 Butyl] -2,7-difluoro-N— (2,2,2-trifluoroethyl) —9Η— 芴 -9 9-methylamine __ (Please read the precautions on the back before filling in this Page) This paper size is in accordance with Chinese National Standard (CNS) Α4 specification (210X297 mm> -153 486469 Α7 Β7 V. Description of the invention (Ιδί) 1'- Α ·

經濟部中央標隼局員工消費合作社印製 於室溫下，將實例3第Β部化合物（8 · 00克， 3 2 · 5毫莫耳）之1 0 0毫升四氫呋喃溶液小心抽空， 而後以氬淨化四次。繼而將攪拌之溶液冷卻至-2 5 °C， 再將正丁基鋰溶液（2 6 · 5毫升，2 · 5莫耳濃度之己 烷液’ 6 6 · 3毫莫耳）於1 5分鐘期間加入。繼而將所 得漿液攪拌1小時，再冷卻至- 7 8 °C，而後將純二溴丁 烷（6 · 0毫升，50 · 0毫莫耳）一次地加入，再令反 應於6小時期間加溫至室溫。另14小時後，將反應混合 物倒至1莫耳濃度氫氯酸（7 0毫升）中，並以乙酸乙酯 萃取兩次。繼而將結合之有機萃取液乾燥（硫酸鈉）及蒸 發。再將半固狀餘留物以己烷碾磨，並予過濾，以得 11· 32克灰白色固狀物。 於室溫下，於氬下，將草醯氯（25毫升，2 . 0莫 耳濃度之二氯甲烷液，5 0毫莫耳）及0 . 5毫升（ 6 · 0毫莫耳）二甲基甲醯胺先後加至上示固狀物（ 1 1 · 0克）之25毫升二氯甲烷漿液中。1小時後，將 反應於低於2 5 °C之溫度下蒸發，令餘留物溶於3 0毫升 四氫呋喃中。繼而於一 1 0 °C下，於氬下，將此溶液於 20分鐘期間加至2，2，2 —三氟乙胺（έ · 10克， (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ 154 一 486469 A7 ____^__B7____ 五、發明説明（152) 6 1 ·〜5毫莫耳）之2 5毫升四氫呋喃溶液中。2小時後 ，使用1 0%檸檬酸溶液令反應中止，再以乙酸乙酯萃取 兩次。繼而將有機萃取液乾燥（硫酸鈉）及蒸發。再藉於 矽膠上進行急驟色層分離法（12x20公分柱，7: 3 二氯甲烷/己烷作爲洗提液）予以純化，即得白色固狀之 標題化合物（9 · 0 3克，由實例3第Β部化合物中得到 60% 產率），熔點 147 - 148 °C。 B · 9 —〔4一〔 〔4一〔 （1 ，1 一二甲基乙氧基） 羰基〕胺基〕一1 一哌啶基〕丁基〕一 2，7 —二氟基一 N — （ 2 , 2 ，2 —三氟乙基）一 9H -芴一 9-甲醯胺 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 於室溫下，於氬下，將實例10第B部化合物（2 · 85克，14 · 2毫莫耳）加至已攪拌之第A部化合物（ 5 · 48克，11 . 9毫莫耳）之20毫升二甲基甲醯胺 溶液中。再將反應加熱至5 0 °C，1 4小時後，使用1 0 %亞硫酸氫鈉溶液令反應中止，並以乙酸乙酯萃取。繼而 將有機萃取液乾燥（硫酸鎂），蒸發及由甲苯中再蒸發兩 次。再藉於矽膠上（2 · 5x1 5公分柱，乙酸乙酯洗提 液）進行急驟色層分離予以純化，即得白色固狀之標題化 合物（6 .23 克，90%)，熔點 152-154 °C。 實例3 2 9 —〔4 一〔4 一〔 （2 -苯氧基苯醯）胺基〕一 1 一哌 啶基〕丁基〕一 N —（2，2，2 —三氟乙基）—9H- 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）^ 155 486469 A7 B7 經濟部中央標隼局員工消費合作社印製 五、發明説明（153 ) 葱一 9-一甲醯胺，單氤氯酸鹽_ ___ 遵循實例1 2第B部之步驟，將2 -苯氧基苯甲酸（ 2 · 0克，9 . 34毫莫耳）轉變成醯基氯，而後與實例 36第D部化合物（4 · 84克，9 · 34毫莫耳）起反 應以得白色固狀物（5.0克）。令產物溶於甲醇（5毫 升）中，而後將0 · 77莫耳濃度氫氯酸之乙醚液（15 毫升）加入。再將溶液蒸發及於真空爐（55°C)中力口^ 過夜，即得白色固狀之標題化合物（5 .1克’ 82%) 〇 熔點· 123 — 127 °C。 MS (ES，+ 離子）：656 (M + H)。 分析· C38H39C 又 F3N302· 〇 · 7H20 之計算值： (：，66·07;Η，5·90;Ν，6·08 ;F，8 · 2 5 實測值：C，66.05;H，5.97;N，5.96;F，8 ·· 2 1。 實例3 3 9 一〔4 一〔 〔4 一（苯醯胺基）一 1 一哌啶基〕丁基〕 一 2，7 — 二氟基—N— (2 ，2，2 -三氟乙基）一 9 Η —芴一 Q —甲醯胺___ 將實例31化合物（2 · 07克，3 · 56毫莫耳） 之1 0毫升4當量濃度氫氯酸之二噁烷溶液攪拌（以氯化 鈣乾燥管保護）3小時。再將溶液於30 °C下蒸發’並令 (請先閲讀背面之注意事項再填寫本頁)Printed at room temperature, the 100 ml tetrahydrofuran solution of the compound of Part 3 (8.0 g, 32.5 mmol) in Part B of Example 3 was printed at room temperature, and then evacuated with argon. Purify four times. Then, the stirred solution was cooled to -2 ° C, and the n-butyllithium solution (26. 5 ml, hexane with a concentration of 2.5 moles' 6 6 · 3 mmoles) was added in 15 minutes. Join during. The resulting slurry was stirred for 1 hour, then cooled to -78 ° C, and then pure dibromobutane (6.0 ml, 50 · 0 mmol) was added in one portion, and the reaction was allowed to warm to 6 hours. Room temperature. After another 14 hours, the reaction mixture was poured into 1 molar hydrochloric acid (70 ml) and extracted twice with ethyl acetate. The combined organic extracts were then dried (sodium sulfate) and evaporated. The semi-solid residue was triturated with hexane and filtered to obtain 11.32 g of an off-white solid. At room temperature, argon chloride (25 ml, 2.0 moles of dichloromethane solution, 50 mmol) and 0.5 ml (6.0 mmol) of dimethyl chloride were added under argon. Methylformamide was successively added to a 25 ml dichloromethane slurry of the solid (11 · 0 g) shown above. After 1 hour, the reaction was evaporated at a temperature below 25 ° C, and the residue was dissolved in 30 ml of tetrahydrofuran. Then at 10 ° C, under argon, add this solution to 2,2,2-trifluoroethylamine (Hand · 10g, (Please read the precautions on the back before filling out this page during 20 minutes). ) This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) _ 154 486469 A7 ____ ^ __ B7____ 5. Description of the invention (152) 6 1 ~~ 5 millimolar) in 25 ml of tetrahydrofuran solution. After 2 hours, the reaction was stopped with a 10% citric acid solution and extracted twice with ethyl acetate. The organic extract was then dried (sodium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (12x20 cm column, 7: 3 dichloromethane / hexane as eluent) to obtain the title compound (9.30 g, as an example) as a white solid. (60% yield in Part B compound), melting point 147-148 ° C. B · 9 — [4— [[4 — [(1,1-dimethylethoxy) carbonyl] amino] -1—piperidinyl] butyl] —2,7—difluoro—N— (2, 2, 2-trifluoroethyl)-9H-hydrazine 9-formamidine (please read the precautions on the back before filling this page) Printed at room temperature by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Add 20 ml of the compound of Part 10 (2.85 g, 14.2 mmol) to the stirred compound of Part A (5.48 g, 11.9 mmol) under argon under argon. Dimethylformamide solution. The reaction was heated to 50 ° C. After 14 hours, the reaction was stopped with a 10% sodium bisulfite solution and extracted with ethyl acetate. The organic extract was then dried (magnesium sulfate), evaporated and evaporated twice from toluene. Then it was purified by flash chromatography on silica gel (2.5x1 5 cm column, ethyl acetate eluent) to obtain the title compound (6.23 g, 90%) as a white solid, melting point 152-154 ° C. Example 3 2 9 — [4— [4 — [(2-phenoxyphenylhydrazone) amino] —1—piperidinyl] butyl] —N— (2,2,2-trifluoroethyl) — 9H- This paper size is in accordance with China National Standard (CNS) A4 (210X297 mm) ^ 155 486469 A7 B7 Printed by the Consumer Cooperatives of the Central Standardization Bureau of the Ministry of Economic Affairs 5. Description of the invention (153) Onion 9-methylformamide , Monofluorenyl chlorate _ ___ Follow the procedure in Example 12, Part B to convert 2-phenoxybenzoic acid (2.0 g, 9.34 mmol) to fluorenyl chloride, and then follow the same procedure as in Example 36. The compound in Part D (4.84 g, 9.34 mmol) reacted to give a white solid (5.0 g). The product was dissolved in methanol (5 ml), and then 0.777 mol of hydrochloric acid in diethyl ether (15 ml) was added. The solution was then evaporated and left in a vacuum oven (55 ° C) overnight to obtain the title compound (5.1 g '82%) as a white solid. Melting point · 123-127 ° C. MS (ES, + ion): 656 (M + H). Analysis · Calculated values of C38H39C and F3N302 · 〇 · 7H20: (:, 66 · 07; Η, 5.90; Ν, 6.08; F, 8 · 2 5 Measured values: C, 66.05; H, 5.97; N , 5.96; F, 8 ·· 2 1. Example 3 3 9-[4-[[4-(Phenylamino)-1-Piperidinyl] butyl]-2,7-difluoro -N- (2,2,2-trifluoroethyl)-9 Η-芴 -Q -formamidine ___ 10 ml of the compound of Example 31 (2.07 g, 3. 56 mmol) with 4 equivalent concentrations of hydrogen Stir the dioxane solution of chloric acid (protected with a calcium chloride drying tube) for 3 hours. Then evaporate the solution at 30 ° C 'and make (Please read the precautions on the back before filling this page)

T 本紙張又度適用中國國家標準（CNS)A4規格（ 210x297公釐）一 156 一 486469T This paper is again applicable to China National Standard (CNS) A4 (210x297 mm)-156-486469

經濟部中夬標隼局員工消費合作社印製 A7 B7五、發明説明（154 ) 所得固狱物再溶於2 0毫升四氫呋喃中。繼而於氬下，將 三乙胺（1 · 24毫升，8 · 9毫莫耳），而後將苯醯氯 (0 · 46毫莫耳，4 · 0毫莫耳）於1〇分鐘期間加至 已冷卻至一 1 0°C之此攪拌溶液中。1小時後，使用飽和 碳酸氫鈉溶液令反應中止，再以乙酸乙酯萃取兩次。而後 將有機萃取液乾燥（硫酸鈉）及蒸發。再藉於矽膠上（5 X20公分柱，1:19甲醇/乙酸乙酯作爲洗提液）進 行急驟色層分離予以純化，由乙酸乙酯/己烷中再結晶後 ，即得白色固狀之標題化合物（1 · 83克，87%產率 )，熔點 177 — 179 °C。 分析· C32H32FsN3〇2· 0 · 25H2〇 之 S十算值： C，65.13;H，5.55; F，16.10;N，7.12 實測值：C，6 5 · 1 0 ; Η，5 · 4 9 ; F，15.85;N，7.12。 ΜΑ (電噴霧，+ 離子）m/e 5 8 6 ( Μ + Η )。 賨例3 4 9 一〔4 一〔4 一（1，3 -二氫基一 1 ’ 3 —二合氧基 —2H -異蚓跺一 2 -基）一1 一哌啶基〕丁基〕一 2， 7 -二氟基—N —（2，2，2 —三氟乙基）一 9H —芴 一 9 一甲醯啤______ 將實例3 1化合物（2 · 02克，3 · 47毫莫耳） 之1 0毫升4當量濃度氫氯酸之二噁烷溶液攪拌（以氯化 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 157 一 (請先閲讀背面之注意事項再填寫本頁) 486469 A7 ^-__B7_ 五、發明説明（I55 ) (請先閱讀背面之注意事項再填寫本頁) 鈣乾燥管保護）3小時。再將溶液於3〇 °C下蒸發，而後 令之分界於飽和碳酸氫鈉溶液及二氯甲烷間。繼而將有機 層分離，乾燥（硫酸鈉）及蒸發以得白色固狀物。將 550毫克（3·71毫莫耳）酞酸酐於氬氣層下加至此 餘留物中。再將固狀物於1 5 0°C下共同熔化6小時β冷 卻後，將所得固狀物由乙酸乙酯/己烷中予以再結晶，卻 得白色固狀之標題化合物（1 · 71克，80%產率）， 熔點 186 -188 °C。 分析· C38H36F5N3〇3· 0 · 1 3H2〇之計算值： C，64.56;H，4·94 ;N，6.87 實測值：C，6 4 · 5 6 ; Η，5 · 0 3 ; N，6 · 8 1 ο MS(電噴霧，+離子）m/e 612·2(M+H) 實例3 5 經濟部中央標隼局員工消費合作社印製 2 ’ 7 —二氟基一 9 一〔4 一〔 〔4 一〔 （2 —苯氧基苯 醯）胺基〕—1—哌啶基〕丁基〕一 N -（2，2，2- 二氣乙基）一 9H —窃一9 一甲酿胺 _ 於義下，將2毫升草醯氯（2 · 0莫耳濃度之二氯甲 烷液，4 · 0毫莫耳）及0 · 1毫升二甲基甲醯胺先後加 至565毫克（2 · 64毫莫耳）2 —苯氧基苯甲酸（ Aldrich)之1 0毫升二氯甲烷溶液中。1小時後，將反 應蒸發，令餘留物（2 -苯氧基苯醯氯）再溶於1 〇毫升 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -158 - (- 6 64 48 經濟部中央標隼局員工消費合作社印製 A7 B7五、發明説明（156) 四氫呋铺中。 將實例31化合物（1 · 00克，1 · 76毫莫耳） 之1 0毫升4當量濃度氫氯酸之二噁烷溶液攪拌（以氯化 鈣乾燥管保護）3小時。再將溶液於30 °C下蒸發，而後 令所得固狀物再溶於1 0毫升四氫呋喃中。於氬下，將三 乙胺（0 . 95毫升，6 · 5毫莫耳）加至此已攪拌且已 冷卻至- 1 0°C之溶液中，繼而將以上所製2 —苯氧基苯 醯氯溶液於1 0分鐘期間加入。1小時後，使用飽和碳酸 氫鈉溶液以令反應中止，再以乙酸乙酯萃取兩次。繼而將 有機萃取液乾燥（硫酸鈉）及蒸發。而後藉於矽膠上藉急 驟色層分離法（5x20公分柱，1 : 19甲醇/乙酸乙 酯作爲洗提液）予以純化，由乙酸乙酯/己烷中予以再結 晶後，即得白色固狀之標題化合物（1 · 01克，85% 產率），熔點1 6 8 - 6 9 °C« 分析· C38H36F5N303之計算值： C，67:35;H，5.35; F，14.02;N，6.20 實測值：C，67.20;H，5.35; F，14.33;N，6.08。 MS (電噴霧，一離子）m/e 676 · 3 (Μ — Η) ο 實例3 6 9 一〔4 一〔4 一（苯醯胺基）一 1 一哌ιι定基〕丁基〕一 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 159 (請先閱讀背面之注意事項再填寫本頁) 486469 A7 ______B7_五、發明説明（I57) Ν— (ι，·2 ，2 ，2 —三氟乙基）一 9H —芴一 9 —甲醯胺 ，單氤氢酸鹽_Printed by the Employees' Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (154) The solidified object obtained was redissolved in 20 ml of tetrahydrofuran. Then under argon, triethylamine (1.24 ml, 8.9 mmol) was added, and then phenylhydrazone (0.46 mmol, 4.0 mmol) was added to it over a period of 10 minutes. This stirred solution has been cooled to 10 ° C. After 1 hour, the reaction was quenched with a saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was then dried (sodium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (5 x 20 cm column, 1:19 methanol / ethyl acetate as eluent). After recrystallization from ethyl acetate / hexane, a white solid was obtained. The title compound (1.83 g, 87% yield), mp 177-179 ° C. Analysis · S32 calculated value of C32H32FsN3 0 2 · 0 · 25H2 0: C, 65.13; H, 5.55; F, 16.10; N, 7.12 Found: C, 6 5 · 1 0; Η, 5 · 4 9; F , 15.85; N, 7.12. MA (electrospray, + ion) m / e 5 8 6 (Μ + Η). Example 3 4 9 one [4 one [4 one (1,3-dihydrol-1'3-dioxy-2H-isoearthyl-2-yl) -1 1 piperidinyl] butyl] -2, 7 -difluoro-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-dimethyl alcohol ______ The compound of Example 3 1 (2.02 g, 3.47 mmol) Mol) 10 ml of 4 equivalents of hydrochloric acid in dioxane solution (using chlorinated paper standards to apply Chinese National Standard (CNS) A4 specifications (210X297 mm)) 157 (please read the notes on the back first) Please fill in this page again for matters) 486469 A7 ^ -__ B7_ V. Description of Invention (I55) (Please read the precautions on the back before filling this page) Calcium drying tube protection) 3 hours. The solution was evaporated at 30 ° C, and then the boundary was between a saturated sodium bicarbonate solution and dichloromethane. The organic layer was then separated, dried (sodium sulfate) and evaporated to give a white solid. 550 mg (3.71 mmol) of phthalic anhydride was added to the residue under an argon layer. The solid was co-melted at 150 ° C for 6 hours. After β cooling, the obtained solid was recrystallized from ethyl acetate / hexane to obtain the title compound (1.71 g as a white solid). , 80% yield), melting point 186 -188 ° C. Analysis · Calculated values for C38H36F5N3〇3 · 0 · 1 3H2〇: C, 64.56; H, 4.94; N, 6.87 Found: C, 6 4 · 5 6; Η, 5 · 0 3; N, 6 · 8 1 ο MS (Electrospray, + ion) m / e 612 · 2 (M + H) Example 3 5 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 2 '7 —difluoro group 9 9 [4 1 [ [4-[(2-phenoxyphenylhydrazone) amino] -1-piperidinyl] butyl] -N- (2,2,2-difluoroethyl) -9H—Ste-9-9 Amines_ Add 2 ml of chlorammonium chloride (2. 0 mols of dichloromethane solution, 4.0 mols) and 0. 1 ml of dimethylformamide to 565 mg (2 64 millimolar) 2-phenoxybenzoic acid (Aldrich) in 10 ml of dichloromethane. After 1 hour, the reaction was evaporated, and the residue (2-phenoxyphenylhydrazone chloride) was re-dissolved in 10 ml. This paper is in accordance with China National Standard (CNS) A4 (210X297 mm) -158-(- 6 64 48 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (156) in tetrahydrofuran. 10 ml of the compound of Example 31 (1.00 g, 1.76 mmol) A solution of 4 equivalents of hydrochloric acid in dioxane was stirred (protected with a calcium chloride drying tube) for 3 hours. The solution was evaporated at 30 ° C, and then the obtained solid was dissolved in 10 ml of tetrahydrofuran. Under argon, triethylamine (0.95 ml, 6.5 mmol) was added to the solution which had been stirred and cooled to -10 ° C, and then the 2-phenoxyphenylhydrazone chloride prepared above was added. The solution was added over a period of 10 minutes. After 1 hour, the reaction was quenched with a saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was dried (sodium sulfate) and evaporated. Then borrowed on silica gel By flash chromatography (5x20 cm column, 1: 19 methanol / ethyl acetate as eluent After purification and recrystallization from ethyl acetate / hexane, the title compound was obtained as a white solid (1.01 g, 85% yield), melting point 1 6 8-6 9 ° C «Analytical · C38H36F5N303 Calculated: C, 67:35; H, 5.35; F, 14.02; N, 6.20 Found: C, 67.20; H, 5.35; F, 14.33; N, 6.08. MS (Electrospray, Ion) m / e 676 · 3 (Μ — Η) ο Example 3 6 9 1 [4 1 [4 1 (phenylamido)-1 piperidinyl] butyl] 1 paper size applies Chinese National Standard (CNS) A4 specifications ( 210X297 mm) _ 159 (Please read the notes on the back before filling this page) 486469 A7 ______B7_V. Description of the invention (I57) Ν— (ι, · 2,2,2—trifluoroethyl) —9H — Thallium 9 —formamidine, monopyridine hydrochloride_

經濟部中央標隼局員工消費合作社印製 於0°C下，將正丁基鋰（2 · 5莫耳濃度，2 11毫 升，5 3 0毫莫耳）之四氫呋喃溶液逐滴加至9 -芴竣酸 (50克，240毫莫耳）之四氫呋喃（1200毫升） 溶液中。再將黃色反應於〇°C下攪拌1小時，而後將1 ， 4 一二溴基丁烷（3 1 · 3毫升，2 6 0毫莫耳）於3 0 分鐘期間逐滴加入。繼而將反應於〇°C下攪拌3 0分鐘， 而後將反應加溫至室溫3 0小時。再將反應以水（3 X 7 5 0毫升）萃取。再將結合之水性層以乙酸乙酯（ 8 0 0毫升）萃取。繼而使用氫，氯酸溶液（1當量濃度， 5 0 0毫升）使水性層成酸性，而後以二氯甲烷（3 χ 7 5 0毫升）萃取。再將結合之有機層於硫酸鎂上乾燥。 蒸發後，即得白色固狀之標題化合物（7 1克，8 5%) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（158 )Printed at 0 ° C by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, the tetrahydrofuran solution of n-butyllithium (2.5 mol concentration, 2 11 ml, 530 mmol) was added dropwise to 9- Perylene acid (50 g, 240 mmol) in tetrahydrofuran (1200 ml). The yellow reaction was stirred at 0 ° C. for 1 hour, and then 1,4-dibromobutane (31. 3 ml, 260 mmol) was added dropwise over 30 minutes. The reaction was then stirred at 0 ° C for 30 minutes, and then the reaction was warmed to room temperature for 30 hours. The reaction was extracted with water (3 × 750 ml). The combined aqueous layer was extracted with ethyl acetate (800 ml). The aqueous layer was then made acidic with a hydrogen, chloric acid solution (1 equivalent concentration, 500 ml), and then extracted with dichloromethane (3 x 750 ml). The combined organic layer was dried over magnesium sulfate. After evaporation, the title compound (71 g, 8 5%) was obtained in the form of a white solid. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (158)

經濟部中夬標準局員工消費合作社印製 於氬下，於〇°C下，將草醯氯（104毫升，2 · 0 莫耳濃度之二氯甲烷液，2 0 8毫莫耳）逐滴加至第A部 酸（6 0克，173毫莫耳）及二甲基甲醯胺（1〇〇微 升）之二氯甲烷（6 0 0毫升）溶液中。再將反應於〇°c 下攪拌10分鐘，而後加溫至室溫，繼而攪拌1 . 5小時 。再將反應於真空中濃縮以得黃色油狀之粗製醯基氯。而 後於0°C下，於氬下，將三乙胺（73毫升，521毫莫 耳）加至2，2，2 —三氟乙胺氫氯酸鹽（25 · 9克， 1 9 1毫莫耳）之二氯甲烷（5 00毫升）懸浮液中，繼 而將粗製醯基氯之二氯甲烷（1 5毫升）溶液逐滴加入。 將反應於0°C下攪拌1小時，以二氯甲烷（.5 0 0毫升） 稀釋，以水（2X30 0毫升），1當量濃度氫氯酸（2 X300毫升），飽和碳酸氫鈉（2x300毫升），及 鹽水（2 X 3 0 0毫升）清洗，再於硫酸鎂上乾燥。蒸發 後乃得8 0克油狀物，將其藉於矽膠（2 · 5公斤）上進 行急驟色層分離法予以純化。而後將粗製產物裝填於二氯 甲烷及己烷之混合液中，並以1 0%乙酸乙酯/己烷（4 升）至15%乙酸乙酯/己烷（2升）至20%乙酸乙酯 /己烷（4升）進行梯度洗提。再結合純溶離份並予蒸發 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 161 486469 A7 B7 五、發明説明（159 ) *即得伯色固狀之標題化合物（52 .5克，71%) (熔點 8 8 - 9 2 °C )。Printed under argon at the Consumers' Cooperative of the China Standards Bureau of the Ministry of Economic Affairs, chloral chloride (104 mL, 2.0 mol concentration of dichloromethane solution, 208 mmol) was dropped at 0 ° C. Add to a solution of Part A acid (60 g, 173 mmol) and dimethylformamide (100 μl) in dichloromethane (600 ml). The reaction was stirred at 0 ° C for 10 minutes, and then warmed to room temperature, followed by stirring for 1.5 hours. The reaction was then concentrated in vacuo to give crude fluorenyl chloride as a yellow oil. Triethylamine (73 ml, 521 mmol) was then added to 2,2,2-trifluoroethylamine hydrochloride (25.9 g, 191 mmol) at 0 ° C under argon. Mol) in dichloromethane (500 ml) suspension, and a solution of the crude fluorenyl chloride in dichloromethane (15 ml) was added dropwise. The reaction was stirred at 0 ° C for 1 hour, diluted with dichloromethane (.500 ml), water (2X300 ml), 1 equivalent hydrochloric acid (2 X300 ml), saturated sodium bicarbonate (2x300 Ml), washed with brine (2 x 300 ml), and dried over magnesium sulfate. After evaporation, 80 g of oil was obtained, which was purified by flash chromatography on silica gel (2.5 kg). The crude product was then filled in a mixture of dichloromethane and hexane, and 10% ethyl acetate / hexane (4 liters) to 15% ethyl acetate / hexane (2 liters) to 20% ethyl acetate Ester / hexane (4 L) was subjected to gradient elution. Combine the pure dissolving fraction and evaporate (please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 161 486469 A7 B7 V. Description of the invention (159) * The title compound was obtained as a solid (52.5 g, 71%) (melting point 8 8-9 2 ° C).

經濟部中央標隼局員工消費合作社印製 將第B部化合物（29 · 5克，69 · 2毫莫耳）， 實例10第B部化合物（14 · 5克，72 · 7毫莫耳） 及無水碳酸鉀（1 1 · 5克，83 · 0毫莫耳）之二甲基 甲醯胺（1 0 0毫升）混合液於5 0 °C下攪拌4 8小時， 濃縮至乾，再置於二氯甲烷（5 0 0毫升）中。而後將溶 液以飽和碳酸氫鈉（3x80毫升）及鹽水（2x80毫 升）清洗，繼而於硫酸鎂上乾燥。蒸發後可得黃色油狀物 ，將其藉於矽膠（6 0 0克）上進行急驟色層分離，裝填 於二氯甲烷中，並以2%甲醇/二氯甲烷（3升）至3% 甲醇/二氯甲烷（4升）梯度洗提而予以純化。而後結合 純溶離份，並予蒸發，即得白色泡沬膠狀之標題化合物（ 3 0 克，8 6 % ) 〇 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 162 一 486469 A7 B7 五、發明説明（160 )The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed the compound of Part B (29.5 g, 69.2 mmol), Example 10 Compound of Part B (14.5 g, 72.7 mmol) and Anhydrous potassium carbonate (11.5 g, 83.0 mmol) in dimethylformamide (100 ml) was stirred at 50 ° C for 4 8 hours, concentrated to dryness, and then placed in Dichloromethane (500 ml). The solution was then washed with saturated sodium bicarbonate (3x80 mL) and brine (2x80 mL), and then dried over magnesium sulfate. After evaporation, a yellow oil was obtained, which was separated on silica gel (600 g) for rapid color layer separation, filled in dichloromethane, and 2% methanol / dichloromethane (3 liters) to 3%. Purification by gradient elution with methanol / dichloromethane (4 liters). Then combine the pure soluble fractions and evaporate to obtain the title compound (30 g, 86%) as a white foam gel. (Please read the precautions on the back before filling this page.) This paper size applies to Chinese national standards (CNS) A4 specifications (210X297 mm)-162-486469 A7 B7 5. Description of the invention (160)

將4當量濃度氫氯酸之二噁烷液（121毫升， 483毫莫耳）加至第C部化合物（30 · 5克， 60 · 4毫莫耳）之二嚼院（120毫升）溶液中。再將 反應於室溫下攪拌4小時，而後於真空中濃縮，即得白色 泡沬固狀之含餘留量二噁烷之標題化合物。 E · 9 -〔4 —〔4-(苯醯胺基）一 1 一呢啶基〕丁 基〕一 N — (2，2，2 —三氟乙基）—9H -荀一 9 一 甲醯胺，單氤氯酸鹽__ 於0 °C下，將苯醯氯（Ο · 4毫升，3 · 40毫莫耳 )逐滴加至第D部化合物及三乙胺（1 · 5毫升， 經濟部中央標隼局員工消費合作社印製 ιϋ· I m HI m m _ - - - - ! m _ _ m^"J (請先閲讀背面之注意事項再填寫本頁) 10 . 8毫莫耳）之二氯甲烷（10毫升）溶液中。再將 反應於0°C下攪拌3 0分鐘。而後將二氯甲烷（2 0 0毫 升）加入，再將溶液以水（2x50毫升），鹽水（2x 5 0毫升）清洗及於硫酸鎂上乾燥。繼而藉於矽膠上（ 100克）進行急驟色層分離，以2·5%甲醇之二氯甲 院液裝填及洗提而予以純化。再結合純溶離份並予蒸發以 得白色固狀物。令產物溶於甲醇（5毫升）中，再將氫氯 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-163 - 486469 A 7 _ B7 五、發明説明（161 ) 酸之乙襬溶液（0 · 77當量濃度，5. 19毫升）加入 。而後將反應於室溫下攪拌1 0分鐘，繼而蒸發至乾。於 真空爐（6 5 °C，72小時）中乾燥後，即得白色固狀之 檫題化合物（1. 3克，72%)。 熔點· 1 3 2 — 1 3 7 °C。 MS (Cj? ，+ 離子）·· 550 (M + H)。 分析.（：32Η35(：文 F3N302· 〇 · 2H20 之計算值： C，65.18;H，6.〇5;N，7.13 ;C 又，6.01;F，9.66 實測值：C，65.45;H，6e〇6;N，6.88 ;C 芡，5.16;F，9.30e 實例3 7 2，3 -二氫基一 2〔1 一〔4 一〔9 一（1 一合氧基戊 基）—9H —荀一 9 一基〕丁基〕一 4 一哌B定基〕一 1H 一異吲跺一 1 一酮，單氪氯酸 (請先閲讀背面之注意事巩再填寫本頁) ii A. 經濟部中央標隼局員工消費合作社印製Add 4 equivalents of hydrochloric acid in dioxane (121 ml, 483 mmol) to the solution in Part C (30 · 5 g, 60 · 4 mmol) of Dioxin (120 ml). . The reaction was stirred at room temperature for 4 hours, and then concentrated in vacuo to give the title compound as a white foamy solid with residual dioxane. E · 9-[4-[4- (phenylamidino)-1-nonidyl] butyl] -N-(2,2,2-trifluoroethyl) -9H -fluorene-9-methyl Amine, monoammonium chlorate __ At 0 ° C, phenylammonium chloride (0 · 4 ml, 3.40 mmol) was added dropwise to the compound in Part D and triethylamine (1.5 ml, Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, I m HI mm _----! M _ _ m ^ " J (Please read the notes on the back before filling this page) 10. 8 millimoles ) In dichloromethane (10 ml). The reaction was stirred at 0 ° C for 30 minutes. Dichloromethane (200 ml) was then added, and the solution was washed with water (2 x 50 ml), brine (2 x 50 ml) and dried over magnesium sulfate. Then, it was purified by flash chromatography on silica gel (100g), and then filled with 2 · 5% methanol in dichloromethane solution. The pure soluble fractions were combined and evaporated to give a white solid. The product was dissolved in methanol (5 ml), and then the size of the hydrochloride paper was adapted to the Chinese National Standard (CNS) A4 specification (210X297 mm) -163-486469 A 7 _ B7 V. Description of the invention (161) Add the solution (0. 77 equivalents, 5.19 ml). The reaction was then stirred at room temperature for 10 minutes and then evaporated to dryness. After drying in a vacuum oven (65 ° C, 72 hours), the title compound (1.3 g, 72%) was obtained as a white solid. Melting point · 1 3 2 — 1 3 7 ° C. MS (Cj ?, + ion) 550 (M + H). Analysis: (: 32Η35 (: calculated value of the text F3N302 · 0 · 2H20: C, 65.18; H, 6.0); N, 7.13; C, 6.01; F, 9.66 found: C, 65.45; H, 6e 〇6; N, 6.88; C 芡, 5.16; F, 9.30e Example 3 7 2, 3 -dihydro- 2 [1-[4-[9-(1 -oxypentyl)-9H-荀A 9 1 base] butyl] 4 a piperidine B adenyl] 1 1 H isoisocyanate 1 1 ketone, monofluoric acid (please read the notes on the back before filling this page) ii A. Central Ministry of Economic Affairs Printed by the Standards Bureau Employee Consumer Cooperative

A(l). 〇TBS (TBS Is SI(CH3)2t-Bu) 於氬下，於0°c下，將l〇 · 5克（0 · 15莫耳） 咪嗤及20 · 7克（0 · 14莫耳）特丁基二甲基甲矽烷 基氯先後加至49毫升（0 · 55莫耳）1，4 一 丁二醇 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X 297公釐） 486469 A7 ______B7 五、發明説明（l62) (請先閲讀背面之注意事項再填寫本頁) 之2 5、毫升二甲基甲醯胺溶液中。再將反應徐緩加溫至室 溫’並攪拌1 8小時後，於此時將反應以乙醚稀釋，以氯 化銨’水，碳酸鈉，鹽水清洗，再予乾燥（硫酸鎂）。所 得無色液態形式之標題化合物（5 0克）乃含有約1 5% 之二甲矽烷基化化合物。 A(2) . | 經濟部中央標隼局員工消費合作杜印製 於氬下，於0°C下，將7 · 3克（108毫莫耳）咪 唑及16 · 7克（64毫莫耳）三苯膦加至8 · 5克（ 42毫莫耳）第A (1)部化合物之50毫升四氫呋喃溶 液中。再將此混合物攪拌4 5分鐘（溶液變爲均勻），並 於此時將16 · 2克（64毫莫耳）碘之50毫升四氫呋 喃液於2 0分鐘期間逐滴加入。再將反應攪拌1小時，以 己烷稀釋及以1莫耳濃度亞硫酸氫鈉，碳酸鈉，鹽水清洗 ，並予乾燥（硫酸鈉）。而後將所得餘留物以乙醚碾磨（ 3次），再予過濾（以移去三苯膦化氧）及蒸發，即得淡 黃色油狀之標題化合物。 薄層色層分離矽膠（4 : 1己烷/乙酸乙酯） R f = 0 · 6 0 。 本紙張尺度適用中國國家標準（CNS ) A4規格（ 210X297公釐）_ 165 __ 4864 經濟部中央標隼局員工消費合作社印製 A7 B7 五、發明説明（163) ” B·A (l). 〇TBS (TBS Is SI (CH3) 2t-Bu) Under argon at 0 ° C, 1.5 g (0. 15 mol) of imidazole and 20.7 g (0 · 14 mol) tert-butyldimethylsilyl chloride is added to 49 ml (0.555 mol) of 1,4-monobutylene glycol. The paper size is applicable to China National Standard (CNS) A4 (210X 297) (Centi) 486469 A7 ______B7 V. Description of the Invention (l62) (Please read the precautions on the back before filling out this page) 2 5. In the dimethylformamide solution. The reaction was slowly warmed to room temperature 'and stirred for 18 hours. At this time, the reaction was diluted with ether, washed with ammonium chloride' water, sodium carbonate, brine, and dried (magnesium sulfate). The title compound (50 g) was obtained in the form of a colorless liquid which contained about 15% of a disilylated compound. A (2). | Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs, printed under argon, at 7 ° C, 7.3 g (108 mmol) imidazole and 16.7 g (64 mmol) ) Triphenylphosphine was added to a solution of 8.5 g (42 mmol) of the compound of Part A (1) in 50 ml of tetrahydrofuran. This mixture was stirred for a further 4 5 minutes (the solution became homogeneous), and at this time, 16.2 g (64 mmol) of iodine in 50 ml of tetrahydrofuran was added dropwise over a period of 20 minutes. The reaction was stirred for another 1 hour, diluted with hexane and washed with 1 mole sodium bisulfite, sodium carbonate, brine, and dried (sodium sulfate). The resulting residue was then triturated with ether (three times), filtered (to remove triphenylphosphine oxide) and evaporated to give the title compound as a pale yellow oil. Thin layer chromatographic silica gel (4: 1 hexane / ethyl acetate) R f = 0 · 60. This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) _ 165 __ 4864 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (163) ”B ·

於氬下，於0°C下，將20·.6毫升（52 · 32毫 莫耳）正丁基鋰（2 . 5莫耳濃度之己烷液）逐滴加至5 克（2 3 · 78毫莫耳）9 一芴羧酸（Aldrich)之20 毫升四氫呋喃溶液中。再將橘紅色陰離子攪拌〇·5小時 ，並於此時將7 · 5克（23 · 78毫莫耳） (依第A部所述之方法製得）逐滴加 入。而後將反應徐緩加溫至室溫，再攪拌3 6小時，此時 將其以1: 1乙酸乙酯/水（2 5 0毫升）混合液稀釋。 繼而將有機相以碳酸氫鈉，鹽水清洗，並予乾燥（硫酸鈉 )及蒸發。再於2 5 0克砂膠上以9 : 1二氯甲院/異丙 醇洗提進行急驟色層分離，即得4 · 9克（5 2%)黃色 油狀之標題化合物。 薄層色層分離：矽膠（9 : 1二氯甲烷/異丙醇） R f = 0 · 5 0 。 (請先閱讀背面之注意事項再填寫本頁) 訂 ίΜ 本紙張尺度適用中國國家標準（〇奶）八4規格（210'/297公釐）-166 486469 A7 B7 五、發明説明（164 )Under argon at 0 ° C, 20.6 ml (52.32 mmol) of n-butyllithium (2.5 moles of hexane) was added dropwise to 5 g (2 3 · 78 millimolar) 9 monohydrocarbamic acid (Aldrich) in 20 ml of tetrahydrofuran. The orange-red anion was stirred for another 0.5 hours, and at this time, 7.5 g (23.78 mmol) (made according to the method described in Part A) was added dropwise. The reaction was then slowly warmed to room temperature and stirred for another 36 hours, at which time it was diluted with a 1: 1 ethyl acetate / water (250 ml) mixture. The organic phase was then washed with sodium bicarbonate, brine, dried (sodium sulfate) and evaporated. Then, 250 g of sand gel was subjected to 9: 1 dichloromethane / isopropanol elution for rapid color layer separation to obtain 4.9 g (52%) of the title compound as a yellow oil. Thin layer color separation: Silicone (9: 1 dichloromethane / isopropanol) R f = 0 · 50. (Please read the precautions on the back before filling this page) Order ίΜ This paper size applies the Chinese national standard (〇 奶) 8 4 specifications (210 '/ 297 mm) -166 486469 A7 B7 V. Description of the invention (164)

將5毫升二甲亞碉加至550毫克（1 · 38毫莫耳 )第B部化合物中。再將反應於氬下，於室溫下攪拌1 8 小時，並於此時將其以乙醚稀釋及以水清洗（3次）。再 於1 0 0克矽膠上以9 5 : 5己烷/乙酸乙酯洗提而予以 急驟色層分離，即得3 4 0毫克（7 0%)淡黃色油狀之 標題化合物。 薄層色層分離：矽膠（95 : 5己烷/乙酸乙酯） R f = 0 · 3 1 0 (請先閲讀背面之注意事項再填寫本頁) 、τ Γ 經濟部中央標隼局員工消費合作社印製5 ml of dimethylarsine was added to 550 mg (1.38 mmol) of Part B compound. The reaction was again under argon and stirred at room temperature for 18 hours, at which time it was diluted with ether and washed with water (3 times). It was then extracted with 100: 5 silica gel with 95: 5 hexane / ethyl acetate and separated by flash chromatography to obtain 340 mg (70%) of the title compound as a pale yellow oil. Thin layer color separation: Silicone (95: 5 hexane / ethyl acetate) R f = 0 · 3 1 0 (Please read the precautions on the back before filling this page), τ Γ Staff consumption of Central Bureau of Standards, Ministry of Economic Affairs Printed by a cooperative

於氬下，於0°C下，將462毫升（1 · 16毫莫耳 )正丁基鋰（2 · 5莫耳濃度之己烷液）逐滴加至3 4 0 毫克（0 · 9 6毫莫耳）第C部化合物之3毫升四氫呋喃 溶液中。再將所得陰離子攪拌0·5小時，並於此時將 140毫升（1 . 16毫莫耳）新蒸餾之戊醯氯（ Aldrich)逐滴加入。而後將反應攪拌2小時’並於此時 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-167 _ 486469 A7 ____B7 _ 五、發明説明（I65) 以乙醚彌釋及使用碳酸氫鈉令反應中止。繼而將有機相以 水，鹽水清洗，並予乾燥（硫酸鈉）及蒸發。再於1 0 0 克矽膠上以95:5己烷/二氯甲烷洗提而予以急驟色層 分離法，即得2 9 0毫克（6 9%)淡黃色油狀之標題化 合物。 薄層色層分離：矽膠（95 : 5己烷/乙酸乙酯） R f = 0 . 3 6 MS (CI—NH3，+ 離子）m/e 3 9 7 ( Μ + Η )0 分析.C24H32〇3S i + 〇 · 1 5 莫耳 Η20 : C，72.20;H，8.15 實測值：C，7 2 · 2 0 ; Η，7 · 8 8 (請先閲讀背面之注意事項再填寫本頁) 訂Under argon, at 0 ° C, 462 ml (1.16 mmol) of n-butyllithium (2.5 ml molar hexane) was added dropwise to 3 40 mg (0 · 9 6 Mmol) in a 3 ml solution of tetrahydrofuran. The resulting anion was stirred for another 0.5 hours, and at this time, 140 ml (1.16 mmol) of freshly distilled pentamidine chloride (Aldrich) was added dropwise. Then the reaction was stirred for 2 hours, and at this time, the paper size applied the Chinese National Standard (CNS) A4 specification (210X297 mm) -167 _ 486469 A7 ____B7 _ 5. Description of the invention (I65) Use ether to dissolve and use hydrogen carbonate Sodium halts the reaction. The organic phase was then washed with water, brine, dried (sodium sulfate) and evaporated. Then, 100 g of silica gel was eluted with 95: 5 hexane / dichloromethane and subjected to a rapid chromatography method to obtain 290 mg (69%) of the title compound as a pale yellow oil. Thin layer chromatographic separation: silica gel (95: 5 hexane / ethyl acetate) R f = 0.36 MS (CI—NH3, + ion) m / e 3 9 7 (M + Η) 0 analysis. C24H32. 3S i + 〇 · 1 5 Mol Η 20: C, 72.20; H, 8.15 Measured value: C, 7 2 · 2 0; Η, 7 · 8 8 (Please read the precautions on the back before filling this page) Order

經濟部中央標隼局員工消費合作社印製 將1毫升5 : 9 5水性氫氟酸/乙睛加至2 0 0毫克 (0·46毫莫耳）第D部化合物中。再將反應於氬下， 於室溫下攪拌3小時，並於此時以乙醚稀釋及以碳酸氫鈉 ，水（3次），鹽水清洗，繼而乾燥（硫酸鎂）及蒸發。 再於50克矽膠上以7:3己烷/乙酸乙酯洗提而予以急 驟色層分離，即得1 2 0毫克（8 1%)淡黃色油狀之標 題化合物。 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-168 一 486469 A7 __B7 五、發明説明（166) 薄層色‘層分離：矽膠（8 : 2己烷/乙酸乙酯） R f 0 . 1 5 。Printed by the Employees' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Add 1 ml of 5: 95 aqueous hydrofluoric acid / acetonitrile to 200 mg (0.46 mmol) of the D compound. The reaction was further stirred under argon at room temperature for 3 hours, at which point it was diluted with ether and washed with sodium bicarbonate, water (3 times), brine, then dried (magnesium sulfate) and evaporated. Then, 50 g of silica gel was eluted with 7: 3 hexane / ethyl acetate and separated by rapid color separation to obtain 120 mg (81%) of the title compound as a pale yellow oil. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) -168 one 486469 A7 __B7 V. Description of the invention (166) Thin layer color 'Layer separation: Silicone (8: 2 hexane / ethyl acetate) R f 0. 1 5.

於氬下，於0°C下，將55毫克（0· 81毫莫耳） 咪唑及1 2 6毫克（0 . 4 8毫莫耳）三苯膦先後加至 120毫克（0 · 37毫莫耳）第E部化合物之1 · 5毫 升四氫呋喃溶液中。再將混合物攪拌〇 . 5小時，並於此 時將1 2 2毫克（0 · 48毫莫耳）碘之1毫升四氫呋喃 逐滴加入。繼而將反應於0 °C下攪拌1小時，於室溫下攪 拌1小時，而後以己烷稀釋及以新鮮亞硫酸氫鈉溶液，碳 酸氫鈉，水，鹽水清洗，並予乾燥（硫酸鎂）及蒸發。再 於2 5克矽膠上以9 : 1‘己烷/乙酸乙酯洗提而予以急驟 經濟部中央標隼局員工消費合作社印製 色層分離，即得1 3 0毫克（8 1%)無色油狀之標題化 合物。 薄層色層分離：矽膠（9 : 1己烷/乙酸乙酯） R f = 0 · 4 0。 G· 2，3 -二氫基一 2 -〔1 一〔4 一〔9 一（1-合氧基戊基）一 9H -芴一 9 一基〕丁基〕一 4 一哌啶基 ]—1H-異蚓跺一1一酮，單氤氯酸鹽_ 169 - (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469 A7 _____B7_____ 五、發明説明（l67) (請先閱讀背面之注意事項再填寫本頁) 於m下，於室溫下，將20毫克（Ο ·1 5毫莫耳） 碳酸鉀及84毫克（0 · 39毫莫耳）實例1第G部化合 物加至1 3 0毫克（0 · 3 0毫莫耳）第F部化合物之1 • 5毫升二甲基甲醯胺溶液中。再將反應攪拌1 8小時， 並於此時倒至水中。而後收集沈澱物，令之溶於乙醚中， 再予乾燥（硫酸鈉）及蒸發以得淡黃色固狀物。令此固狀 物溶於乙醚中，再以305毫升（0 · 30毫莫耳）氫氯 酸（1莫耳濃度之乙醚液）處理。繼而將乙醚潷析出，再 收集固狀物並予乾燥1 8小時（5 0 °C，於真空下），即 得1 1 5毫克（74%)淡黃色固狀之標題化合物》 熔點· 9 6 - 1 〇 〇 °C。 薄層色層分離：矽膠（95:5二氯甲烷/異丙醇+1% 氫氧化銨） R f = 0 · 4 6。 MS (ES;氫氧化銨，+離子）m/e 521 (M + Η )。 分析· C35H40N2〇2 HCJ2 + 0 · 5 莫耳 H2〇 : 經濟部中央標準局員工消費合作社印製 C，74.25;H，7.48:N，4.95 實測值：（：，74·24;Η，7·45;Ν，4·98 ο 實例3 8 2，3 -二氫基一 2 -〔1 (1 一 合氧基 一3，3 —二苯 甚）一 4 一哌啶基〕一 1 Η -異吲跺-1 一酮_ 本紙張尺^適用中國國家標準（CNS)A4規格（210x297公釐）-170 - " 486469 A7 B7 經濟部中央標隼局員工消費合作杜印製 五、發明説明（168 ) 於垄溫下’將草醯氯之二氯甲烷液（2 · 0莫耳濃度 ，1 。66毫升，3 · 32毫莫耳）逐滴加至3，3 -二 苯基丙酸（500毫克，2 · 21毫莫耳）及二甲基甲醯 胺（1滴）之二氯甲烷（5毫升）溶液中。加完後，逸出 之氣體乃持續起泡10分鐘。繼而將反應於室溫下攪拌 6 0分鐘，而後於真空中濃縮以得粗製油狀物。再於〇°C 下，於氬下，將實例1第G部化合物（4 3 4毫克， 2 · 00毫莫耳）之二氯甲烷（2毫升）溶液逐滴加至粗 製醯基氯及三乙胺（1 · 4毫升，10 · 0毫莫耳）之二 氯甲烷（1 0毫升）溶液中。繼而將反應於〇°C下攪拌 1 0分鐘。再將二氯甲烷（1 0 0毫升）加入以將反應稀 釋，而後將所得溶液以水（40毫升），飽和碳酸氫鈉溶 液（40毫升），鹽水（40毫升）清洗及於硫酸鎂上乾 燥。蒸發後可得粗製膠狀物。將其藉於矽膠（1 0 0克） 上進行急驟色層分離，以2.5%甲醇之二氯甲烷液裝填 及洗提而予以純化。而後結合純溶離份並予蒸發，即得灰 色固狀之標題化合物（6 10毫克，72%)。 熔點.Γ66 — 169 °C。 MS (FAB，+ 離子）：425 (M+H) 分析· c28h28n2o2· 1 · 1H20 之計算值： C，75.68;H，6.85;N，6.30 實測值：C，75.50;H，6.45;N，6.24 (請先閲讀背面之注意事項再填寫本頁) 衣. 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 171 486469 A7 B7 五、發明説明（l69 ) ” 實例3 q 〔1 一〔4 一〔9一〔（丙胺基）羰基〕一 9H —芴一 9 一基〕丁基〕一 3 —哌啶基〕胺基甲酸，苯甲酯，單氫氯 酸鹽_Under argon at 0 ° C, add 55 mg (0.81 mmol) of imidazole and 126 mg (0.4 8 mmol) of triphenylphosphine to 120 mg (0.37 mmol) Ear) Compound 1.5 in tetrahydrofuran. The mixture was stirred for another 0.5 hours, at which time 122 ml (0.48 mmol) of 1 ml of tetrahydrofuran in iodine was added dropwise. The reaction was then stirred at 0 ° C for 1 hour and at room temperature for 1 hour, then diluted with hexane and washed with fresh sodium bisulfite solution, sodium bicarbonate, water, brine, and dried (magnesium sulfate). And evaporation. It was then stripped on 25 g of silicon gel with 9: 1 'hexane / ethyl acetate and separated by printing the color layer of the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economics to obtain 130 mg (81%) colorless. The title compound as an oil. Thin layer chromatographic separation: silica gel (9: 1 hexane / ethyl acetate) R f = 0 · 40. G · 2,3 -dihydrol-2-[1-[4-[9-(1-Hydroxypentyl) -9H -fluorene -9 -yl] butyl] -4 -piperidinyl]- 1H-Iso-earthone-one-one ketone, monoammonium chlorate _ 169-(Please read the precautions on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 486469 A7 _____B7_____ V. Description of the invention (l67) (Please read the notes on the back before filling this page) Under m, at room temperature, 20 mg (0 · 1 5 mmol) potassium carbonate and 84 mg (0 · 39 millimoles) Example 1 Part G compound was added to 130 mg (0.30 mmol) of Part F compound 1. 5 ml of dimethylformamide solution. The reaction was stirred for an additional 18 hours and poured into water at this point. The precipitate was then collected, dissolved in ether, dried (sodium sulfate) and evaporated to give a pale yellow solid. This solid was dissolved in diethyl ether and treated with 305 ml (0. 30 mmol) of hydrochloric acid (1 mole of diethyl ether solution). Diethyl ether was then decanted, and the solid was collected and dried for 18 hours (50 ° C under vacuum) to obtain 115 mg (74%) of the title compound as a pale yellow solid. Melting point · 9 6 -100 ° C. Thin layer color separation: Silicone (95: 5 dichloromethane / isopropanol + 1% ammonium hydroxide) R f = 0 · 4 6. MS (ES; ammonium hydroxide, + ion) m / e 521 (M + Η). Analysis · C35H40N2 0 HCJ2 + 0 · 5 Mohr H2 0: Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, C, 74.25; H, 7.48: N, 4.95 Found: (:, 74 · 24; Η, 7 · 45; Ν, 4.98 ο Example 3 8 2,3-dihydrol-2-[1 (1 -synoxy-3,3-diphenyl even) -4 -piperidinyl] -1 fluorene -iso Indine-1 monoketone_ This paper ruler ^ Applies to China National Standard (CNS) A4 (210x297 mm) -170-& 486 469 A7 B7 Printed by the staff of the Central Bureau of Standards, Ministry of Economic Affairs, Consumer Consumption 168) At a ridge temperature, dichloromethane solution of chloramphenicol (2.0 mol concentration, 1.66 ml, 3.32 mmol) was added dropwise to 3,3-diphenylpropionic acid ( 500 mg, 2.21 mmol) and dimethylformamide (1 drop) in dichloromethane (5 ml). After the addition, the escaping gas continued to bubble for 10 minutes. The reaction was then allowed to proceed It was stirred at room temperature for 60 minutes, and then concentrated in vacuo to obtain a crude oil. Then at 0 ° C, under argon, the compound of Part G of Example 1 (4 3 4 mg, 2. 00 mmol) Ear) of dichloromethane (2 L) solution was added dropwise to a solution of crude fluorenyl chloride and triethylamine (1.4 ml, 10.0 mmol) in dichloromethane (10 ml). The reaction was then stirred at 0 ° C for 1 0 minutes. Dichloromethane (100 ml) was added to dilute the reaction, and the resulting solution was washed with water (40 ml), saturated sodium bicarbonate solution (40 ml), brine (40 ml) and sulfuric acid. It is dried over magnesium. After evaporation, a crude gum is obtained. It is purified by flash chromatography on silica gel (100 g), and purified by filling and eluting with 2.5% methanol in dichloromethane. Then combined Purely dissolve and evaporate to obtain the title compound (6 10 mg, 72%) as a gray solid. Melting point. Γ66 — 169 ° C. MS (FAB, + ion): 425 (M + H) Analysis · c28h28n2o2 · 1 · Calculated value of 1H20: C, 75.68; H, 6.85; N, 6.30 Found: C, 75.50; H, 6.45; N, 6.24 (Please read the notes on the back before filling this page) Standards apply to Chinese National Standard (CNS) A4 specifications (210X297 mm) 171 486469 A7 B7 V. Description of invention (l69) "Example 3 q [1-[4-[9-[(propylamino) carbonyl] -9H-fluorene-9-yl] butyl] -3-piperidinyl] carbamic acid, benzyl methyl ester, monohydrochloride Acid salt_

經濟部中央標隼局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 將實例5第A部化合物（2 · 34克，6 · 90毫莫 耳）及_啶酸乙酯（1 · 3毫升，8 · 28毫莫耳）之二 甲基甲醯胺（3 · 5毫升）混合液於氬下，於6 0°C下加 熱2 2小時，而後冷卻至室溫。再於減壓下移去溶劑。令 所得橘色餘留物溶於二氯甲烷（5 0毫升）中，以飽和碳 酸氫鈉（2x 1 5毫升）及鹽水（20毫升）清洗，繼而 於硫酸鈉上乾燥。蒸發後可得3·6克橘色膠狀物，令之 溶於最小量二氯甲烷中，再藉於矽膠（1 7 5克）上進行 急驟色層分離並以2 %甲醇/二氯甲烷洗提而予以純化， 以得2 · 6 5克沾染約2 0莫耳％二甲基甲醯胺之產物。 令產物溶於乙酸乙酯（6 0毫升）中，以水（3 X 2 0毫 升）及鹽水（2 0毫升）清洗，繼而於硫酸鈉上乾燥。蒸 發後’即得琥珀色油狀之標題化合物（2 · 38克，7 5 % ) 〇 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 172 486469 A7 B7 五、發明説明（170 ) B·Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Example 5 Compound of Part A (2.334 g, 6.90 mmol) and ethyl picolinate (1.3 ml, 8.28 mmol) of dimethylformamide (3.5 ml) was mixed under argon, heated at 60 ° C for 2 hours, and then cooled to room temperature. The solvent was removed under reduced pressure. The resulting orange residue was dissolved in dichloromethane (50 ml), washed with saturated sodium bicarbonate (2 x 15 ml) and brine (20 ml), and then dried over sodium sulfate. After evaporation, 3.6 g of orange gum was obtained, which was dissolved in a minimum amount of dichloromethane, and then separated by flash chromatography on silica gel (175 g) and separated with 2% methanol / dichloromethane. Eluted and purified to obtain 2.65 g of product contaminated with about 20 mole% dimethylformamide. The product was dissolved in ethyl acetate (60 ml), washed with water (3 x 20 ml) and brine (20 ml), and then dried over sodium sulfate. After evaporation ', the title compound was obtained as an amber oil (2.38 g, 75%). ○ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 172 486469 A7 B7. 5. Description of the invention (170 ) B ·

(請先閱讀背面之注意事項再填寫本頁) 耳）加至第A部化合物（2 · 37克，5 · 15毫莫耳） 之乙酸乙酯（1 0毫升）及乙醇（1 5毫升）混合溶液中 。再將混合物於室溫下氫化（氣球）1 . 5小時，通過寅 氏鹽中過濾，繼而以乙酸乙酯（3 X 2 0毫升）清洗。而 後將濾液於真空中濃縮，即得淡黃色油狀之標題化合物（ 2 .42 克，100%)。 C. , η 經濟部中央標準局員工消費合作社印製(Please read the precautions on the back before filling out this page) Ear) Ethyl acetate (10 ml) and ethanol (15 ml) added to the compound of Part A (2 · 37 g, 5 · 15 mmol) In mixed solution. The mixture was further hydrogenated (balloon) at room temperature for 1.5 hours, filtered through Yin's salt, and then washed with ethyl acetate (3 x 20 ml). The filtrate was then concentrated in vacuo to give the title compound (2.42 g, 100%) as a pale yellow oil. C., η Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

於氬下，將水性氫氧化鉀（5 · 6毫升，1當量濃度 ，5。6毫莫耳）加至第8部化合物（2.17克， 4 · 7 0毫莫耳）之四氫呋喃（1 〇毫升）溶液中。再將 雙相混合物於室溫下攪拌4小時，而後於5 0 °C下加熱 4 8小時，繼而將反應冷卻至室溫，再以1當量濃度氫氯 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 173 _ 經濟部中央標隼局員工消費合作社印製 486469 A7 _________B7__ 五、發明説明（Π1) 酸酸化'成Ρ Η 1 · 5而後將混濁反應以水（3 0毫升）稀 釋及以氯仿（3 X 1 0 0毫升）萃取，繼而於硫酸鈉上乾 燥。蒸發後，即得泡沬白色固狀之標題化合物（2 · 2克 ，1 0 0 % 粗製）。 D . 〔 1 一〔4 一〔9 一〔（丙胺基）鐵基〕一 9Η — 芴一 9 一基〕一 丁基〕一 3 —哌啶基〕胺基甲酸，苯甲酯 ，單氤氯酸鹽 ___ 於氬下，將二苯基磷醯基化疊氮（1 8 4微升， 0 · 857毫莫耳）加至第C部化合物（336毫克， 0 · 714毫莫耳）及三乙胺（238微升，1 · 71毫 莫耳）之二噁烷混濁懸浮液中。再將混合物於8 0°C下加 熱2小時（加熱開始後立刻看到氮氣釋出）。而後將苄醇 (367微升，3 · 57毫莫耳）加入，再將反應於80 °C下加熱過夜。繼而將反應冷卻至室溫，再將溶劑於減壓 下蒸餾出。令所得餘留物分界於二氯甲烷（2 0毫升）及 飽和碳酸氫鈉（5毫升）間。再將有機層以鹽水（5毫升 )清洗及於硫酸鈉上乾燥。蒸發後可得7 6 0毫克黃色油 狀物，再將其藉於矽膠（5 0克）上進行急驟色層分離並 以3%甲醇/二氯甲烷洗提而予以純化，即得2 1 5毫克 無色油狀物。 令游離胺溶於乙醚（3毫升）中，再以0 . 77當量 濃度氫氯酸之乙醚（3毫升）液處理。而得將白色沈澱物 過濾，以乙醚（2 X 3毫升）清洗，繼而於髙度真空下， 本紙張尺度適用中國國家標準（(：奶）八4規格（210'乂 297公釐)_174 一 一 (請先閱讀背面之注意事項再填寫本頁)Under argon, aqueous potassium hydroxide (5.6 ml, 1 equivalent, 5.6 mmol) was added to tetrahydrofuran (10 ml of compound 8) (2.17 g, 4.70 mmol). ) In solution. The biphasic mixture was stirred at room temperature for 4 hours, and then heated at 50 ° C for 4 8 hours. The reaction was then cooled to room temperature, and then the Chinese National Standard (CNS) was applied to the paper at 1 equivalent concentration. A4 specifications (210X297 mm) _ 173 _ Printed by the Consumers 'Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 486469 A7 _________B7__ V. Description of the invention (Π1) Acidification of acid into' P Η 1 · 5 ) Dilute and extract with chloroform (3 × 100 ml), then dry over sodium sulfate. After evaporation, the title compound was obtained as a white solid (2.2 g, 100% crude) as a white solid. D. [1-[4-[9-[(propylamino) ironyl]-9-fluorene-9-9-yl]-butyl]-3-piperidinyl] carbamic acid, benzyl methyl ester, monofluorenyl chloride Acid salt ___ Add diphenylphosphonium azide (184 microliters, 0.857 millimoles) to Part C compound (336 mg, 0.714 millimoles) under argon and Triethylamine (238 µl, 1.71 mmol) in a dioxane turbid suspension. The mixture was heated at 80 ° C for another 2 hours (nitrogen evolution was observed immediately after heating started). Then benzyl alcohol (367 μl, 3.57 mmol) was added and the reaction was heated at 80 ° C overnight. The reaction was then cooled to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was delimited between dichloromethane (20 ml) and saturated sodium bicarbonate (5 ml). The organic layer was washed with brine (5 mL) and dried over sodium sulfate. After evaporation, 760 mg of a yellow oil was obtained, which was then purified by flash chromatography on silica gel (50 g) and purified by eluting with 3% methanol / dichloromethane to give 2 1 5 Mg of colorless oil. The free amine was dissolved in diethyl ether (3 ml) and treated with 0.777 equivalents of hydrochloric acid in diethyl ether (3 ml). The white precipitate must be filtered, washed with diethyl ether (2 X 3 ml), and then under a high degree of vacuum, the paper size applies the Chinese national standard ((: milk) 8 4 specifications (210 '乂 297 mm) _174 a One (Please read the notes on the back before filling this page)

486469 A7 _____B7_ _ 五、發明説明（172 ) 於5 f°C下乾燥過夜，即得白色泡沬固狀之標題化合物（ 173毫克，42%)。 MS (ES) 540 CM + H] 分析。C34H42C^N303· 〇 · 3H20 之計算值： C，7 0 · 2 2 ; Η，7 · 3 8 ; N，7 · 2 3 實測值：C，70.11;H，7.24;N，7.09 〇 實例4 0 9 一〔4 —〔4 一（2，3 —二氫基一 1 一合氧基一 1H 一異丨_ 一 2 -基）一1 一哌b定基〕丁基〕—N — (2， 2—，2 —三氟乙基）—9H 一芴一 9 一甲醯胺，氣氯酸鹽 A. (請先閲讀背面之注意事項再填寫本頁)486469 A7 _____B7_ _ V. Description of the invention (172) Dry at 5 f ° C overnight to obtain the title compound (173 mg, 42%) as a white foam. MS (ES) 540 CM + H]. Calculated value of C34H42C ^ N303 · 〇 · 3H20: C, 7 0 · 2 2; Η, 7 · 3 8; N, 7 · 2 3 Found: C, 70.11; H, 7.24; N, 7.09 〇 Example 4 0 9 1 [4 — [4 1 (2,3 —dihydrol — 1 —oxyl — 1H — iso — — — 2 —yl) — 1 — piperidine] butyl] —N — (2, 2 —, 2 —trifluoroethyl) —9H 1-9 9-methaneamine, chlorate A. (Please read the precautions on the back before filling this page)

經濟部中央標隼局員工消費合作社印製 於室溫下，將20 · 0毫升（40毫莫耳）2莫耳濃 度草醯氯之二氯甲烷液及3 0毫升二甲基甲醯胺先後加至 已攪拌之10 · 0克（33 · 5毫莫耳）實例5第A部第 一段所製化合物之1 0 0毫升二氯甲烷溶液中。當將溶劑 蒸發且將半固態餘留物泵唧（約1毫米壓力）0 · 5小時 之時，令反應於室溫下攪拌2小時。而後藉加入3 0 0毫 升乙醚令餘留物溶解，再冷卻至0°C，繼而將混合物以 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 175 一 ~ ' 486469 A7 ___B7_ 五、發明説明（Π3 )Printed at room temperature by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, 20 ml (40 millimolar) of 2 moles of chlorpyrrolium dichloromethane solution and 30 ml of dimethylformamide Add to a stirred solution of 100.0 g (33.5 mmol) of the compound prepared in the first paragraph of Part A, Example 5, 100 ml of dichloromethane. When the solvent was evaporated and the semi-solid residue was pumped (about 1 mm pressure) for 0.5 hours, the reaction was allowed to stir at room temperature for 2 hours. Then add 300 ml of diethyl ether to dissolve the residue, and then cool to 0 ° C, and then apply the Chinese National Standard (CNS) A4 specification (210X297 mm) to the paper standard _ 175 ~ ~ 486469 A7 ___B7_ V. Description of the invention (Π3)

7 ·：?'·0克（67毫莫耳）2，2，2-三氟乙胺處理， 再加溫至室溫。而後將混合物以1 5 0毫升乙酸乙酯及 1 0 0乙酸乙酯0 . 5莫耳濃度氫氯酸稀釋。再將諸層分 離’將有機相乾燥（硫酸鈉）及濃縮。而後將餘留物藉於 矽膠（250克）上進行急驟柱色層分離並以1 : 9乙酸 乙酯/己烷（800毫升），繼而1:5乙酸乙酯/己烷 (1升）洗提而予以純化。繼而收集純溶離份，再予濃縮 ’即得9 · 25克（73%)白色固狀之標題化合物。 熔點：8 7 — 8 9 〇C (請先閱讀背面之注意事項再填寫本頁)7 ·: · '0 g (67 mmol) treated with 2,2,2-trifluoroethylamine and warmed to room temperature. The mixture was then diluted with 150 ml of ethyl acetate and 100 ethyl acetate at 0.5 mol hydrochloric acid. The layers were separated 'and the organic phase was dried (sodium sulfate) and concentrated. The residue was then subjected to flash column chromatography on silica gel (250 g) and washed with 1: 9 ethyl acetate / hexane (800 ml), followed by 1: 5 ethyl acetate / hexane (1 liter). It is then purified. Then, the pure soluble fractions were collected and concentrated again to obtain 9.25 g (73%) of the title compound as a white solid. Melting point: 8 7 — 8 9 〇C (Please read the precautions on the back before filling this page)

經濟部中央標隼局員工消費合作社印製 於室溫下，將4 · 〇 〇克（1 8 · 5 1毫莫耳）實例 1第G部化合物及2 · 4 1克（17 · 50毫莫耳）碳酸 鉀加至已攪拌之6 · 54克（17 · 22毫莫耳）第A部 化合物之6毫升二甲基甲醯胺溶液中。再將反應混合物加 溫至4 0°C，而後令之攪拌2 0小時。繼而將混合物以 2 0 0毫升水及2毫升1莫耳濃度氫氧化鈉溶液（pH = 1 1 )稀釋。再藉過濾法收集白色固狀物並予乾燥，即得 10,0克（100%)標題化合物。 薄層色層分離矽膠（5 : 95 : 1甲醇/二氯甲烷/氨） i紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ " 486469 經濟部中央標隼局員工消費合作社印裝 A7 B7五、發明説明（174) R f = Ό . 3 5 ^ c。 9 一〔4 一〔4 一（2，3 —二氫基一 1 一 合氧基 一 1 Η -異吲p呆一 2 -基）一 1 一哌啶基〕丁基一 N -（ 2 ，2 ，2 —三氟乙某）一9Η —芴一 9 一甲醯胺_ 將10 · 00克（約17毫莫耳）第Β部化合物之 80毫升乙醇懸浮液以〇·5克10%鈀/碳處理，再置 於氫氣層（氣球壓）下。當通過寅氏鹽墊中過濾並濃縮之 時，將反應混合物攪拌2 5小時。繼而將餘留物以溫水碾 磨，即得9 ·0克（93%)白色固狀之標題化合物。 熔點：143 — 146 °C。 薄層色層分離砂膠（5 : 9 5 :1甲醇/二氯甲院/氣） R f = 0 · 3 5。 D · 9 -〔4 -〔4一（2，3 —二氫基一 1 一 合氧基 —1H -異口引晚一 2 —基）一1 一哌B定基〕丁基〕—N — (2，2，2 —三氟乙基）一9H —芴一 9 一甲醯胺，氫 氯酸鹽____ 將9 · 00克（約16毫莫耳）第B部化合物之 2 0 0毫升乙醚懸浮液以8毫升（3 2毫莫耳）4莫耳濃 度氫氯酸之二噁烷液處理，再將反應混合物於氮氣層下攪 拌1小時。而後將反應混合物過濾，再收集白色固狀物， 繼而將固狀物於4 0°C下，於真空下乾燥，即得9 · 0克 (93%)白色固狀之標題化合物。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X公釐） 177 - 486469 A7 _B7_ 五、發明説明（l75 ) 熔點广1 3 9 — 1 4 1 °C。 薄層色層分離矽膠（5 : 95 : 1 甲醇/二氯甲烷/氨 )R f = 0 · 3 5。 MS (ES，+ 離子）m/e 562 (M + H) 。 分析·C33H35N3〇2F3Cj2之S十算值. C，66.27;H，5.9 0;N，7.30 ;F，9 · 5 3 實測值：C，6 6 · 5 3 ; Η，5 · 8 2 ; N，6 · 7 8 ;F，8 · 9 9 〇 實例4 1Printed at room temperature by the Consumers Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 4.00 g (18.51 mmol) of the compound from Part 1 of Example 1 and 2.41 g (17.50 mmol) Ear) Potassium carbonate was added to a stirred solution of 6.54 g (17.22 mmol) of Part A compound in 6 ml of dimethylformamide. The reaction mixture was warmed to 40 ° C and allowed to stir for 20 hours. The mixture was then diluted with 200 ml of water and 2 ml of a 1 molar sodium hydroxide solution (pH = 1 1). The white solid was collected by filtration and dried to obtain 10,0 g (100%) of the title compound. Thin layer color separation silicone (5: 95: 1 methanol / dichloromethane / ammonia) i Paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) _ " 486469 Employees' Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Printing A7 B7 V. Description of the invention (174) R f = Ό. 3 5 ^ c. 9 1 [4 1 [4 1 (2,3-dihydrol-1 1-oxyl-1 1 Η-isoindapyr-2-yl)-1 1-piperidinyl] butyl-N-(2, 2, 2-trifluoroethyl)-9Η-芴-9-Methylamine __ 1 00 grams (about 17 millimoles) of a compound of Part B in 80 ml of ethanol suspension with 0.5 g of 10% palladium / Carbon treatment, and then placed under a hydrogen layer (balloon pressure). When filtered through a Yin's salt pad and concentrated, the reaction mixture was stirred for 25 hours. The residue was then triturated with warm water to obtain 9.0 g (93%) of the title compound as a white solid. Melting point: 143 — 146 ° C. Thin layer color separation mortar (5: 9 5: 1 methanol / dichloromethane / gas) R f = 0 · 3 5. D · 9-[4-[4-((2,3-dihydroyl-1, 1-oxyl-1H-isobutyryl-2-yl) -1, 1-piperidinyl] butyl] —N — ( 2,2,2-trifluoroethyl) -9H-fluorene-9 monomethylamine, hydrochloride ____ Put 9.0 g (approximately 16 mmol) of Part B compound in 200 ml of ether The suspension was treated with 8 ml (32 mmol) of 4 moles of hydrochloric acid in dioxane, and the reaction mixture was stirred under a nitrogen blanket for 1 hour. The reaction mixture was then filtered and a white solid was collected. The solid was then dried at 40 ° C under vacuum to give 9.0 g (93%) of the title compound as a white solid. (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X mm) 177-486469 A7 _B7_ V. Description of the invention (l75) Wide melting point 1 3 9 — 1 4 1 ° C. Thin layer chromatographic silica gel (5: 95: 1 methanol / dichloromethane / ammonia) R f = 0 · 3 5. MS (ES, + ion) m / e 562 (M + H). Analyze · S value of C33H35N3〇2F3Cj2. C, 66.27; H, 5.90; N, 7.30; F, 9 · 5 3 Found: C, 6 6 · 5 3; Η, 5 · 8 2; N, 6 · 7 8; F, 8 · 9 9 〇 Example 4 1

9 一〔4 一〔4 一（2，3 -二氫基一 1 一合氧基一 1Η 一異d引晚一 2 -基）一 1 一喊u定基〕丁基〕一 Ν -（2， 2，2 —三氟乙基）一9Η —芴一 9 一甲醯胺，氤氯酸鹽 Α. …I9 1 [4 1 [4 1 (2,3 -dihydrol-1 1 -oxyl 1 1 -one isomer 2 -yl) -1 1 -u-yl] butyl] -N-(2, 2,2 —trifluoroethyl) —9Η— 芴 —9—methaneamine, chlorochloride A.… I

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 於室溫下，將2 · 44克（18 · 51毫莫耳）實例 2第Α部化合物及1 . 59克（11 . 30毫莫耳）碳酸 鉀加至已攪拌之4 · 00克（9 · 38毫莫耳）實例36 第B部化合物之6毫升二甲基甲醯胺溶液中。再將反應混 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 178 _ 486469 A7 ___ B7五、發明説明（I76) 合物加<溫至5 0°C，而後令之攪拌1 8小時。繼而將混合 物以2 0 0毫升水及2毫升1莫耳濃度氫氧化鈉溶液（ P H= 1 1 )稀釋。再藉過濾法收集白色固狀物並予乾燥 ，即得4.50克標題化合物。 B · 9 —〔4 一〔4 一（2，3 -二氫基一 1 一合氧基一 1H -異蚓p朵一 2-基）一 1 一哌啶基〕丁基〕一 N -（ 2，2，2 —三氟乙基）一 9H —芴一 9 一甲醯胺，氫氯 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印裂 將4 · 00克（約9 · 0毫莫耳）第A部化合物之 2 0 0毫升乙醚懸浮液以8毫升（3 2毫莫耳）4莫耳濃 度氫氯酸之二噁烷液處理，再將反應混合物於氮氣層下攪 拌1小時。繼而將反應混合物過濾，再收集乳白色固狀物 ，而後將固狀物於40 °C下，於真空下乾燥，即得3。8 克（7 3 % )標題化合物。 熔點：139-141 °C。 MS (ES，+ 離子）m/e 562 (M + H)。 分析· C33H35N302F3Ci之計算值： C，66·27;Η，5.90 ;N，7.03 實測值：C，65.87;H，6.14;N，6.71 實例4 2 — 5 0 遵循本文所述之步驟，即製得下列化合物。 本紙張尺度適用>國國家標準（〇灿）八4規格（210、/297公釐） ~ 一 1 一 486469 A 7 ___B7_ 五、發明説明（l77 ) 實例4 2 (請先閱讀背面之注意事項再填寫本頁) 9 一〔4一〔3—（苯醯胺基）一1 一哌啶基〕丁基 〕一Ν—丙基一 9Η -芴一 9 一甲醯胺 MS(ES)510(M + H) 〇 分析。C33H39N302· 0 · 2H2〇之計算值： C，7 7 · 2 2 ; Η，7 · 7 4 ; N，8 · 1 9 實測值·· C，7 7 · 1 2 ; Η，7 · 5 8 ; Ν，8 · 1 6 〇 實例4 3 9 一 〔 4 — C 3 一 (1 > 3 —— 二氫基 一 1 一 合氧基 一 2 Η 一異D引口朵 一 2 — 基 )一 1 — 哌啶基〕 丁基〕 一 Ν — 丙基 一 9 Η — 荀 — 9 一 甲醯胺 MS ( E S ) 5 3 6 ( Μ + Η ) 〇 分析 ° C 3 3 Η 3 7 Ν 3 〇 3 • 0 • 2 Η 2 0之計算值： C 9 7 5 • 7 2 Η 贅 6 · 9 9 ; Ν， 7 • 7 9 實測值 C 9 7 5 • 6 8 ； Η 6 . 7 8 ； Ν ， 7 .6 8 〇 經濟部中央標隼局員工消費合作社印製 實例4 4 9 一〔4 一〔4 一（2，3 —二氫基一 1 一合氧基一 1Η 一異蚓跺一 2 -基）一 1 一哌啶基〕丁基〕—Ν -（2， 2 ，3 ，3 ，4，4 一七氟丁基）一 9Η —苟一 9 —甲醯 本紙張尺度適用中國國家標準（〇奶）八4規格（210乂297公釐）一18() 486469 A7 B7 五、發明説明（l78) 胺，單m氯酸鹽 熔點：122 — 13 2°C。 (請先閱讀背面之注意事項再填寫本頁) MS(ES，+ 離子）m/e 6 6 2 ( Μ + Η )。 分析· c 33H 35〇2N 3F 7C j? · 0 · 8 H 2〇之計算值： C，59.04 ;Η，5·17;Ν，5.90 實測值：C，5 9 · 0 4 ; Η，5 · 0 4 ; N，5 · 9 0 ο 實例4 5 9 一〔4——〔〔4 一〔 （1 ，1 一二甲基乙氧基）羰基〕 胺基〕一 1 一哌啶基〕丁基〕一 3 ，6 —二氟基一Ν —（ 2 ，2 ，2 —三氟乙基）一 9Η —芴一 9 一甲醯胺 熔點：59 — 64 °C。 MS (FAB，M+H) + = m/ z 582 + 分析· C30H36F5N303· 0 · 2當量己烷之計算值： C，62·. 58;Η，6·53;Ν，7·02 實測值：C，6 2 · 4 1 ; Η，6 · 5 5 ; Ν，6 · 8 4 經濟部中央標隼局員工消費合作社印製 ο 實例4 6Printed by the Consumers Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). At room temperature, place 2.44 g (18.51 mmol) of the compound of Part A of Example 2 and 1. 59 grams (11.30 millimoles) of potassium carbonate was added to a stirred 4.00 grams (9.38 millimoles) of the compound of Part 36 in Example 36 in 6 ml of dimethylformamide. The paper size of the reaction mixture is then applied to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 178 _ 486469 A7 ___ B7 V. Description of the invention (I76) Compound addition < temperature to 50 ° C, and then order Stir for 18 hours. The mixture was then diluted with 200 ml of water and 2 ml of a 1 molar sodium hydroxide solution (PH = 1 1). The white solid was collected by filtration and dried to obtain 4.50 g of the title compound. B · 9 — [4-[4-(2,3-dihydrol-1 1-oxyl- 1H-isopyridyl- 2-yl) -1 1-piperidinyl] butyl] -N-( 2,2,2- Trifluoroethyl) 9H — 9-9 Methylamine, Hydrochloride (Please read the precautions on the back before filling out this page) The Central Government Bureau of the Ministry of Economic Affairs and the Consumer Cooperatives will print 4 · 00 g (about 9.0 mmol) of a 200 ml ether suspension of the compound of Part A was treated with 8 ml (32 mmol) of 4 moles of hydrochloric acid in dioxane, and then The reaction mixture was stirred under a nitrogen blanket for 1 hour. The reaction mixture was then filtered, and a milky white solid was collected, and the solid was dried at 40 ° C under vacuum to obtain 3.8 g (73%) of the title compound. Melting point: 139-141 ° C. MS (ES, + ion) m / e 562 (M + H). Analysis · Calculated values of C33H35N302F3Ci: C, 66 · 27; Η, 5.90; N, 7.03 Found: C, 65.87; H, 6.14; N, 6.71 Example 4 2-5 0 Obtained by following the steps described in this article The following compounds. Applicable to this paper's standard: National Standard (〇 Chan) 8 4 specifications (210, / 297 mm) ~ 1 1 486469 A 7 ___B7_ V. Description of the invention (l77) Example 4 2 (Please read the precautions on the back first (Fill in this page again) 9- [4- [3- (Phenylamino)-1-piperidinyl] butyl] -N-propyl-9Η- 芴 -9-methylformamide MS (ES) 510 ( M + H) o Analysis. Calculated value for C33H39N302 · 0 · 2H2〇: C, 7 7 · 2 2; Η, 7 · 7 4; N, 8 · 19 · Measured value · · C, 7 7 · 1 2; Η, 7 · 5 8; Ν, 8 · 1 6 〇 Example 4 3 9 one [4 — C 3 one (1 > 3 —— dihydrol-1 1-oxyl 2 2 Η one iso-D-introducer 2 2 -yl) 1 —Piperidinyl] butyl] —N—propyl—9 Η — 荀 — 9—methylformamide MS (ES) 5 3 6 (Μ + Η) 〇 Analysis ° C 3 3 Η 3 7 Ν 3 〇3 • Calculated values of 0 • 2 Η 2 0: C 9 7 5 • 7 2 Η redundant 6 · 9 9; Ν, 7 • 7 9 found C 9 7 5 • 6 8; Η 6. 7 8; Ν, 7. 6 8 〇 Example of printing by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4 4 9 1 [4 1 [4 1 (2,3-dihydrol-1 1-oxyl-1 1-isoloxanthrene 2-based) -1 -piperidinyl] butyl] -N-(2, 2, 3, 3, 4, 4, 4 heptafluorobutyl)-9Η-Gou 9-Formamidine This paper size applies Chinese national standards (0 milk ) 8 4 specifications (210 乂 297 mm) 18 () 486469 A7 B7 V. Description of the invention ( l78) Amine, monom-chlorate Melting point: 122-13 2 ° C. (Please read the notes on the back before filling this page) MS (ES, + ion) m / e 6 6 2 (Μ + Η). Analysis · c 33H 35〇2N 3F 7C j? · 0 · 8 H 2 0 Calculated: C, 59.04; H, 5.17; N, 5.90 Found: C, 5 9 · 0 4; H, 5 · 0 4; N, 5 · 9 0 ο Example 4 5 9-[4 —— [[4-[(1,1 -dimethylethoxy) carbonyl] amino] -1 -piperidinyl] butyl ] 3,6-difluoro-N- (2,2,2-trifluoroethyl)-9Η- 芴 -9-Methylformamide Melting point: 59-64 ° C. MS (FAB, M + H) + = m / z 582 + analysis · C30H36F5N303 · 0 · 2 equivalents of calculated hexane: C, 62 ·. 58; H, 6.53; N, 7.02 Measured value: C, 6 2 · 4 1; Η, 6 · 5 5; Ν, 6 · 8 4 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Instance 4 6

1一〔4-〔4 一（1 ，3 -二氫基一 1-合氧基一 2Η -異π引跺一 2 -基）一 1 一哌啶基〕丁基〕一 2 -甲基一 Ν —（2 ，2 ，2 —三氟乙基）一1Η —芘一 1-甲醯胺 熔點：124 — 126 °C 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 1Q1 486469 A7 B7 五、發明説明（179) MS ”m / z ( E S，+ 離子）5 2 6 · 3 ( M + Η ) 分析· c3〇h34f3n3o2之計算值： (請先閲讀背面之注意事項再填寫本頁) C，67.55;H，6.5 2;N，7.99 ;F，1 0 · 8 4 實測值：C，6 7 · 8 0 ; Η，6 · 5 3 ; N，7 · 8 9 ;F，1 0 · 7 5 ° 實例4 7 9 —〔4一〔4 一（1 ，3 -二氫基一 1 一 合氧基—2Η 一異d引晚一 2 -基）—1—呢陡基〕丁基〕一 Ν — (2， 2，3，3 ，3 —五氟丙基）一9Η —荀一 9 一甲醯胺， 單氫氯酸鹽1- [4- [4-((1,3-dihydrol-1-oxyl- 2Η-isoπ-fluorene-2-yl)-1-piperidinyl] butyl] -2-methyl- Ν — (2,2,2—trifluoroethyl) —1Η— 芘 —1-methaneamine Melting point: 124 — 126 ° C The paper size applies to the Chinese National Standard (CNS) A4 (210X297 mm) _ 1Q1 486469 A7 B7 V. Description of the invention (179) MS ”m / z (ES, + ion) 5 2 6 · 3 (M + Η) Analysis · Calculated value of c3〇h34f3n3o2: (Please read the notes on the back before filling in (This page) C, 67.55; H, 6.5 2; N, 7.99; F, 1 0 · 8 4 Found: C, 6 7 · 8 0; Η, 6 · 5 3; N, 7 · 8 9; F, 1 0 · 7 5 ° Example 4 7 9 — [4— [4— (1,3 -dihydrol—1—oxy] —2Η—isobutyryl—2—radical] —1—neosyl] Butyl] -N — (2, 2, 3, 3, 3-pentafluoropropyl) — 9Η — 荀 -9 9 methylamine, monohydrochloride

熔點：130-144 °C MS (ES，+ 離子）m/z 5 7 8 ( Μ + Η ) 分析· C33H35N3〇2F5C5 + 1 · 2Η2〇之計算值： C，60.98;H，5.63;N，6.27 ;F，1 4 · 1 8 經濟部中央標隼局員工消費合作社印製 實測值：C，61.34;H，5.48;N，6.08 ;F，1 3 · 6 9 ° 實例4 8 1一〔4一〔4 — (1 ，3 -二氫基一 1 一合氧基一 2H 一異D3丨晚一 2 -基）一 1—呢π定基〕丁基〕—N -（2 ’ 2 ，2 —三氟乙基）一 1H —喆一1 一甲醯胺 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）一 182 - 486469 A7 _ B7__ 五、發明説明（180 )Melting point: 130-144 ° C MS (ES, + ion) m / z 5 7 8 (M + Η) Analysis · Calculated for C33H35N3〇2F5C5 + 1 · 2Η2〇: C, 60.98; H, 5.63; N, 6.27 ; F, 1 4 · 1 8 Printed measured values by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs: C, 61.34; H, 5.48; N, 6.08; F, 1 3 · 6 9 ° Example 4 8 1 1 [4 1 [4 -— (1,3-dihydrol-1, 1-oxyl-2H, iso-D3, late-2-yl), 1-n-pyridyl] butyl] -N- (2'2, 2--3 Fluoroethyl) 1H — 1H 1 Methylamidine The paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 1 182-486469 A7 _ B7__ V. Description of the invention (180)

熔點：〜6 2 — 6 5 °C MS m/z (ES，一離子）510 (M-H)， 5 5 6 ( Μ + H C Ο 2-) 分析.C29H32F3N302· 0 · 1 6Η2〇之計算值： C，67.70;H，6.33;N，8.17 ;F，1 1 . 0 8 實測值：C，67.70;H，6.26;N，7.94 ;F，1 0 · 6 2。 實例4 9 9 一〔 4 一〔4一（苯醯胺基）-1 一哌啶基〕丁基〕一 3，6 —二氟基一 N— (2，2，2-三氟乙基）一 9H 一荀一9一甲醯胺 MS (FAB，M + H) + 586 + 分析· C32H32F5N3O2· Η 2 〇 · 0.15CH2C^2之計算值： 經濟部中央標隼局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) C，62.65;H，5.61;N，6.82 實測值：C，62.52;H，5.56;N，6.67 ο 實例5 0 3，6 -二氣基一 9 一〔4一〔4 一〔 （2 -苯氧基苯醯 )胺基〕一 1 一哌啶基〕丁基〕一 Ν -（2，2，2 -三 氟乙基）一9Η—^—9—甲醯胺 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）二183 __ 486469Melting point: ~ 6 2 — 6 5 ° C MS m / z (ES, monoion) 510 (MH), 5 5 6 (Μ + HC Ο 2-) Analysis. C29H32F3N302 · 0 · 1 6Η2〇 Calculated value: C , 67.70; H, 6.33; N, 8.17; F, 1 1.08 Found: C, 67.70; H, 6.26; N, 7.94; F, 1 0 · 62. Example 4 9 9- [4-[[4-((phenylamino))-1-piperidinyl] butyl]-3,6-difluoro-N- (2,2,2-trifluoroethyl) -9H 荀 9-Methylamine amine MS (FAB, M + H) + 586 + analysis · C32H32F5N3O2 · Η 2 〇 · 0.15CH2C ^ 2 Calculated: Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (Please Read the precautions on the back before filling in this page) C, 62.65; H, 5.61; N, 6.82 Found: C, 62.52; H, 5.56; N, 6.67 ο Example 5 0 3, 6-two gas radicals 9 1 [4— [4 — [(2-phenoxyphenylhydrazone) amino] —1—piperidinyl] butyl] —N— (2,2,2-trifluoroethyl) —9Η — ^-9 —The formamide is applicable to Chinese National Standard (CNS) A4 (210X297 mm) II 183 __ 486469

A7 ___B7_ 五、發明説明（181) 熔點：〜1 2 4 - 2 6 °C MS(FAB，M + H)m/z 678 + 分析。C38H36F5N303之計算值： C，67.35;H，5.3 5;N 實測值：C，67.38;H，5.62;N 6 2 0 9 2 眚例5 1至1 6 7 下列化合物係藉下述之自動操縱步驟製得。 自動操縱步驟_ 供製備醯胺用之Robotics法 (請先閲讀背面之注意事項再填寫本頁)A7 ___B7_ V. Description of the invention (181) Melting point: ~ 1 2 4-2 6 ° C MS (FAB, M + H) m / z 678 + analysis. Calculated values for C38H36F5N303: C, 67.35; H, 5.3 5; N Measured values: C, 67.38; H, 5.62; N 6 2 0 9 2 Example 5 1 to 1 6 7 The following compounds are obtained by the following automatic manipulation steps be made of. Automated Procedures_ Robotics Method for the Preparation of Amidine (Please read the precautions on the back before filling this page)

、1T 經濟部中央標準局員工消費合作社印製, 1T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

0 I Η A ·二胺初始物質之製備： 將二胺雙氫氯酸鹽（化合物X) (10克，19 .3 毫莫耳）之氯仿（4 0 0毫升）溶液以1當量濃度氫氧化 鉀溶液（3x 1 0 0毫升）清洗。再將有機層以水（2x 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -184 - 經濟部中央標準局員工消費合作社印製 486469 A7 _____B7 五、發明説明（182) 1 0『毫升），鹽水（2 X 1 0 0毫升）清洗及於硫酸鎂 上乾燥。蒸發後即得無色油狀之游離二胺（8 · 8克， 10 0%)。 B·供自動操縱化合物用之一般實驗： 下列者爲根據上述方程式經由羧酸與二胺之偶合作用 以供合成醯胺之一般步驟。這些酸-胺偶合作用及接續之 純化作用係使用Zymark Benchmate®自動操縱系統使用 IBM PC以操作程式及書寫Benchmate步驟來進行。 在16毫升X100毫米試管內裝入1 .6毫莫耳， 4當量R5C 02H酸，再使用塑膠帽/柱夾寬鬆地封蓋。 Benchmate®乃繼而於管上進行下列步驟： 1) 將1毫升（81毫克，0 · 6毫莫耳，1 · 5當 量）81毫克/毫升1-羥基苯並三咪水合物之二甲基甲 醯胺溶液加入。 2) 將1毫升（75毫克，0 · 6毫莫耳，1 · 5當 量）7 5毫克/毫升二異丙基碳化二亞胺之二氯甲烷溶液 加入。 3) 將1毫升（178毫克，0 · 4毫莫耳，1當量 )17毫克/毫升二胺之二氯甲烷溶液加入。 4) 將注射管以3毫升二氯甲烷清洗， 5) 藉於速度3下渦流15秒以將試管內容物混合。 衣-- (請先閲讀背面之注意事項再填寫本頁) 訂 d 486469 A7 B7 經濟部中央標準局員工消費合作社印裝 五、發明説明（183) 測定無初始胺殘留；10%甲醇+1%氫氧化銨之二氯甲 烷液，碘）。 繼而將反應混合內容物藉Benchmate ®機械人促成之 離子交換色層分離法予以純化。下列者爲供Benchmate® 進行偶合產物之純化作用所發展出之標準步驟。 1 )將Variari固相萃取柱（1 · 5克，S C X陽離子 交換）以1 0毫升甲醇以0 . 2 5毫升/秒之速調理， 2 )將反應內容物以〇 . 〇 5毫升/秒之速裝填於柱 上， 3) 將此柱以2x10毫升甲醇以0.1毫升/秒之 速清洗， 4) 將此柱以1 0毫升0 . 1莫耳濃度氨之甲醇液以 0 · 1毫升/秒之速清洗， 5 )以4毫升2莫耳濃度氨之甲醇液洗提此柱，再以 0·1毫升/秒之速收集至配衡接收管中， 6 )以1毫升2莫耳濃度氨之甲醇液洗提此柱，再以 0·1毫升/秒之速收集至相同之配衡接收管中， 7 )將注射管以5毫升甲醇潤洗。 所有之溶液/溶劑衍生物均繼1.8毫升空氣之後且 於裝載反應內容物至離子交換柱之後使用10秒之推動延 遲時間。 將產物溶液於Savant Speed Vac (約2毫米汞柱5小 時）上濃縮，再更進一步暴露至高度真空下（0 0 1 5 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -186 - 486469 A7 B7 五、發明説明（184) 毫米汞‘柱，1 4小時）以移去最終溶劑殘留物，以得產物 Y ’其乃藉高效能液體色層分離及質譜法予以特徵化。 (請先閲讀背面之注意事項再填寫本頁) C ·製備性高效能液體色層分離純化作用 如果偶合反應係與帶有鹼性取代基（例如吡啶基或胺 基）之羧酸進行，則上示第B部分所離析出之產物γ乃沾 染初始之酸。 將由S C X柱中洗提及速度真空濃度後之樣品於甲醇 中再構成，再將小量三氟乙酸（1滴）加入。而後將產物 Y藉使用下列狀況進行製備性色層分離予以純化： 溶劑A : 10%甲醇，90%水，0 · 1%三氟乙酸0 I Η A · Preparation of the diamine starting material: Diamine dihydrochloride (Compound X) (10 g, 19.3 mmol) in chloroform (400 ml) was added at a concentration of 1 equivalent Wash with potassium solution (3x 100 ml). Then the organic layer is water (2x this paper size applies the Chinese National Standard (CNS) A4 specification (210X297mm) -184-printed by the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 486469 A7 _____B7 V. Description of the invention (182) 1 0 "ML", brine (2 X 100 mL) was washed and dried over magnesium sulfate. Free diamine (8.8 g, 100%) was obtained as a colorless oil after evaporation. B. General Experiments for Automatically Manipulating Compounds: The following are the general steps for synthesizing amidine through the coupling of a carboxylic acid and a diamine according to the above equation. These acid-amine couplings and subsequent purifications were performed using a Zymark Benchmate® robotic system using an IBM PC to operate programs and write Benchmate steps. A 16 ml X 100 mm test tube was filled with 1.6 mils, 4 equivalents of R5C 02H acid, and capped loosely with a plastic cap / column clip. Benchmate® then performed the following steps on the tube: 1) 1 ml (81 mg, 0.6 millimoles, 1.5 equivalents) of 81 mg / ml dimethylformaldehyde 1-hydroxybenzotriimide hydrate Add amidine solution. 2) Add 1 ml (75 mg, 0.6 millimoles, 1.5 equivalents) of 75 mg / ml diisopropylcarbodiimide in dichloromethane. 3) Add 1 ml (178 mg, 0.4 mmol, 1 equivalent) of 17 mg / ml diamine in dichloromethane. 4) Wash the injection tube with 3 ml of dichloromethane. 5) Vortex at speed 3 for 15 seconds to mix the contents of the tube. Clothing-(Please read the precautions on the back before filling this page) Order 486469 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (183) Determination of no initial amine residues; 10% methanol + 1% Dichloromethane solution of ammonium hydroxide, iodine). The reaction mixture was then purified by ion-exchange chromatography using a Benchmate ® robot. The following are standard procedures developed for the purification of Benchmate® coupling products. 1) Condition a Variari solid-phase extraction column (1.5 g, SCX cation exchange) with 10 ml of methanol at a rate of 0.5 ml / s, 2) adjust the reaction content at 0.05 ml / s Quickly pack the column, 3) wash the column with 2x10 ml of methanol at a rate of 0.1 ml / sec, 4) load the column with 10 ml of a 0.1 molar methanol solution of ammonia at 0.1 ml / sec Wash at a fast speed, 5) elute the column with 4 ml of 2 mol methanol solution of ammonia, and collect it into a balance receiving tube at a rate of 0.1 ml / s, 6) at 1 ml of 2 mol ammonia solution The column was eluted with methanol solution, and then collected into the same balance receiving tube at a rate of 0.1 ml / sec. 7) The injection tube was rinsed with 5 ml of methanol. All solution / solvent derivatives followed a push delay time of 10 seconds following 1.8 ml of air and after loading the reaction contents onto the ion exchange column. The product solution was concentrated on Savant Speed Vac (approximately 2 mm Hg for 5 hours), and then further exposed to high vacuum (0 0 1 5 (Please read the precautions on the back before filling out this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -186-486469 A7 B7 V. Description of the invention (184) mmHg 'column, 14 hours) to remove the final solvent residue to obtain the product Y' which is borrowed High-performance liquid chromatographic separation and mass spectrometry were used to characterize it. (Please read the notes on the back before filling in this page) C. Preparative high-performance liquid chromatography separation and purification If the coupling reaction is performed with a carboxylic acid with a basic substituent (such as pyridyl or amine), then The product γ isolated in Part B above is contaminated with the initial acid. Reconstitute the sample after washing from the S C X column to the speed and vacuum concentration in methanol, and then add a small amount of trifluoroacetic acid (1 drop). The product Y was then purified by preparative chromatographic separation using the following conditions: Solvent A: 10% methanol, 90% water, 0.1% trifluoroacetic acid

溶劑B : 90%甲醇，10%水，0 . 1%三氟乙酸 柱：YMC ，ODS-A ，SH-363-5 ，3〇x 250 毫米 I.D· S — 5 微米，12〇Α，Νο · 30 2 5356A 經濟部中央標準局員工消費合作社印裝 初始％ B : 0 % 最終 ％ B : 1 0 0 % 梯度時間：3 0分鐘 流速： 25毫升/分 · 波長： 2 2 0 n m 衰減： 9(1.28 AUFS) 本紙張尺度適用中國國家標準（CNS)A4規格（210x297公釐）- 187 - 486469 A7 _______B7__ 五、發明説明（185) 將’·純溶離份結合再予濃縮以得純化之產物Y，其乃藉 高效能液體色層分離+質譜予以特徵化。 請注意實例5 1至1 6 7中有關僅帶有兩個以單鍵鍵 結至氮上之取代基之結構方面，第三個取代基通常爲氫， 但結構中並未明示。此外，請注意實例5 1至1 6 7中有 關帶有氧及硫且僅具有一個以單鍵鍵結之取代基之結構方 面，第二個取代基通常爲氫，但結構中並未明示。 實例號碼 分子結構 分析資料 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製Solvent B: 90% methanol, 10% water, 0.1% trifluoroacetic acid column: YMC, ODS-A, SH-363-5, 30 × 250 mm ID · S — 5 microns, 12〇Α, NO 30 2 5356A Initial printing of consumer cooperatives printed by employees of the Central Standards Bureau of the Ministry of Economic Affairs B: 0% Final% B: 1 0 0% Gradient time: 30 minutes Flow rate: 25 ml / min · Wavelength: 2 2 0 nm Attenuation: 9 ( 1.28 AUFS) This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm)-187-486469 A7 _______B7__ V. Description of the invention (185) The pure soluble fractions are combined and concentrated to obtain the purified product Y, It is characterized by high performance liquid chromatography + mass spectrometry. Note that with respect to the structure in Examples 5 1 to 16 with only two substituents bonded to nitrogen with a single bond, the third substituent is usually hydrogen, but the structure is not explicitly stated. In addition, please note that in Examples 5 1 to 1 6 regarding the structure having oxygen and sulfur and having only one substituent bonded with a single bond, the second substituent is usually hydrogen, but the structure is not explicitly stated. Example number Molecular structure Analytical data (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 188 486469 A7 B7 五、發明説明（I86) 53 54This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 188 486469 A7 B7 V. Description of invention (I86) 53 54

ο m/z585 (M+H) m/z 619 (Μ+Η) (請先閲讀背面之注意事項再填寫本頁) 55 α ο Νο m / z585 (M + H) m / z 619 (Μ + Η) (Please read the notes on the back before filling out this page) 55 α ο Ν

α m/z 619 (Μ+Η)α m / z 619 (Μ + Η)

經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210X297公釐）_ ι89 _ 486469 A7 B7 五、發明説明（187) 56Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This paper is sized according to the Chinese National Standard (CNS) A4 (210X297 mm) _ ι89 _ 486469 A7 B7 V. Description of the invention (187) 56

m/z 580 (M+H) 57m / z 580 (M + H) 57

經濟部中央標準局員工消費合作社印製 58Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 58

oJC^0 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 19〇 一 m/z 580 (M+H) m/z 580 (M+H) (請先閲讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（l88) 59oJC ^ 0 This paper size applies to China National Standard (CNS) A4 (210X297 mm)-1901 m / z 580 (M + H) m / z 580 (M + H) (Please read the precautions on the back first (Fill in this page again) 486469 A7 B7 V. Description of Invention (l88) 59

Ο m/z 563 (ΜΗ) 60Ο m / z 563 (ΜΗ) 60

m/z 618 (Μ+Η) (請先閲讀背面之注意事項再填寫本頁) :裝m / z 618 (Μ + Η) (Please read the precautions on the back before filling this page):

經濟部中夬標準局員工消費合作社印製 訂 61Printed by Zhongli Standard Bureau Staff Consumer Cooperative, Ministry of Economic Affairs 61

m/z 618 (Μ+Η) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）—191 486469 A7 B7 五、發明説明（189 ) 62m / z 618 (Μ + Η) This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm)-191 486469 A7 B7 V. Description of the invention (189) 62

m/z 618 (M+H) 63m / z 618 (M + H) 63

m/z 642 (M+H) (請先閲讀背面之注意事項再填寫本頁) ·裝· 64m / z 642 (M + H) (Please read the precautions on the back before filling out this page) · Equipment · 64

m/z 642 (M+H) 訂 經濟部中央標準局員工消費合作社印製 65m / z 642 (M + H) Order 65 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

N FN F

m/z 564 (M+H) o 本紙張尺度適用中國國家標準（CNS)A4規格（210X297公釐）_ 192 _ 486469 A7 B7 五、發明説明（190 ) 66m / z 564 (M + H) o This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) _ 192 _ 486469 A7 B7 V. Description of the invention (190) 66

m/z 564 (M+H)m / z 564 (M + H)

Ο 67Ο 67

m/z 564 (M+H) (請先閲讀背面之注意事項再填寫本頁) ·裝· 68 經濟部中央標準局員工消費合作社印製 69m / z 564 (M + H) (Please read the notes on the back before filling out this page) · Equipment · 68 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 69

m/z 578 (M+H) m/z 606 (M+H) 訂 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 一 486469 A7 B7 五、發明説明（W1 ) 70 71m / z 578 (M + H) m / z 606 (M + H) The size of the paper is applicable to Chinese National Standard (CNS) A4 (210X297 mm)-486469 A7 B7 V. Description of the invention (W1) 70 71

m/z 595 (M+H) m/z 595 (M+H) (請先閲讀背面之注意事項再填寫本頁) o 72m / z 595 (M + H) m / z 595 (M + H) (Please read the notes on the back before filling this page) o 72

NN

m/z 563 (M-H) 0 73 經濟部中央標準局員工消費合作社印製m / z 563 (M-H) 0 73 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

m/z 591 (M-H)m / z 591 (M-H)

F n、Ovs 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 194 _ 486469 A7 B7 五、發明説明（192 ) 74F n, Ovs This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) _ 194 _ 486469 A7 B7 V. Description of the invention (192) 74

m/z 540 (M+H) 75m / z 540 (M + H) 75

m/z 556 (M+H) (請先閲讀背面之注意事項再填寫本頁) ··裝. 76 Λρ 〇m / z 556 (M + H) (Please read the precautions on the back before filling in this page) ·· Installation. 76 Λρ 〇

Ν η m/z 539 (M+H) 訂 經濟部中央標準局員工消費合作社印製 77Ν η m / z 539 (M + H) Order Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 77

m/z 554 (M+H) 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 一 486469 A7 B7 五、發明説明（l93 ) 78m / z 554 (M + H) This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) _ One 486469 A7 B7 V. Description of Invention (l93) 78

m/z 590 (M+H) 79m / z 590 (M + H) 79

m/z 570 (M+H) (請先閲讀背面之注意事項再填寫本頁)m / z 570 (M + H) (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 80 81Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 80 81

m/z 569 (M+H) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）一 196 _ m/z 591 (M+H) 486469 A7 B7 五、發明説明（194 ) 82 83m / z 569 (M + H) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)-196 _ m / z 591 (M + H) 486469 A7 B7 V. Description of the invention (194) 82 83

經濟部中央標準局員工消費合作社印製 84Printed by Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs 84

m/z 684 (M+H) α m/z 567 (Μ+Η) m/z 631 (M+H) (請先閲讀背面之注意事項再填寫本頁) 85m / z 684 (M + H) α m / z 567 (Μ + Η) m / z 631 (M + H) (Please read the notes on the back before filling this page) 85

m/z 565 (ΜΗ) 本紙張尺度適用中國國家標準（CNS)A4規格（210Χ297公釐）_ 197 _ 486469 A7 B7 五、發明説明（l95) 86m / z 565 (ΜΗ) This paper size applies to Chinese National Standard (CNS) A4 (210 × 297 mm) _ 197 _ 486469 A7 B7 V. Description of the invention (l95) 86

m/z 565 (ΜΗ) 87m / z 565 (ΜΗ) 87

m/z 619 (Μ+Η) α (請先閲讀背面之注意事項再填寫本頁)m / z 619 (Μ + Η) α (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 88 89Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 88 89

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〇 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）一 198 m/z 629 m/z 568 (M+H) 486469 A7 B7 五、發明説明（196 ) 90〇 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)-198 m / z 629 m / z 568 (M + H) 486469 A7 B7 V. Description of the invention (196) 90

m/z 540 (M+H) 91m / z 540 (M + H) 91

m/z 583 (M+H) (請先閲讀背面之注意事項再填寫本頁)m / z 583 (M + H) (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 92 93Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 92 93

m/z 601 々'丨V (M+H)m / z 601 々 '丨 V (M + H)

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）^ 19g _ m/z 567 (M+H) 486469This paper size applies to China National Standard (CNS) A4 (210X297 mm) ^ 19g _ m / z 567 (M + H) 486469

A7 B7 五、發明説明（丨97 ) 94 95 96 97A7 B7 V. Description of the invention (丨 97) 94 95 96 97

m/z 603 (M+H)m / z 603 (M + H)

αα

〇- 本紙張尺度適用中國國家標準（CNS〉A4規格（ 210X297公釐）_ 2G〇 _ m/z 586 (M+H) m/z 643 (M+H) m/z 625 (M+H) (請先閣讀背面之注意事項再填寫本頁) 486469 Α7 Β7 五、發明説明（198 ) 98〇- This paper size applies Chinese national standard (CNS> A4 size (210X297mm) _ 2G〇_ m / z 586 (M + H) m / z 643 (M + H) m / z 625 (M + H) (Please read the precautions on the back before filling out this page) 486469 Α7 Β7 V. Description of the invention (198) 98

m/z 587 (M+H) α Ν 99m / z 587 (M + H) α Ν 99

αχ m/z 610 (Μ+Η) 100αχ m / z 610 (Μ + Η) 100

m/z 581 (Μ+Η) αm / z 581 (Μ + Η) α

訂 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 101Order (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 101

m/z 591 (Μ+Η) 本紙張尺度適用中國國家標準（CNS)A4規格（ 21.0X297公釐）_ 201 - 486469 A7 B7 五、發明説明（199 ) 102m / z 591 (Μ + Η) This paper size is applicable to Chinese National Standard (CNS) A4 (21.0X297 mm) _ 201-486469 A7 B7 V. Description of the invention (199) 102

7m.h)21 1037m.h) 21 103

m/z 617 (M+H) (請先閱讀背面之注意事項再填寫本頁)m / z 617 (M + H) (Please read the notes on the back before filling this page)

經濟部中央標隼局員工消費合作社印製 104 105Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 104 105

αΝ 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）_ 202 m/z 676 (M+H) m/z 649 (M+H) 486469 A7 B7 五、發明説明（ 200 ) 106αΝ This paper size applies Chinese National Standard (CNS) A4 specification (21.0X297 mm) _ 202 m / z 676 (M + H) m / z 649 (M + H) 486469 A7 B7 V. Description of the invention (200) 106

m/z 594 (M+H) 107m / z 594 (M + H) 107

d m/z 641 (M+H) (請先閱讀背面之注意事項再填寫本頁) 108d m / z 641 (M + H) (Please read the notes on the back before filling this page) 108

m/z 626 (M+H) 109 經濟部中央樣準局員工消費合作社印製m / z 626 (M + H) 109

m/z 640 (M+H) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 203 - 486469 A7 B7 五、發明説明（2〇l ) 110m / z 640 (M + H) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) _ 203-486469 A7 B7 V. Description of the invention (2〇l) 110

m/z 655 (M+H)m / z 655 (M + H)

111111

m/z 656 (M+H)m / z 656 (M + H)

(請先閲讀背面之注意事項再填寫本頁) .©^衣·(Please read the notes on the back before filling out this page). © ^ 衣 ·

經濟部中央標準局員工消費合作社印製 112 113Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 112 113

m/z 528 (M+H) m/z 556 (M+H) 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）—204 _ 486469 A7 B7 五、發明説明（2〇2 ) 114m / z 528 (M + H) m / z 556 (M + H) The size of the paper is applicable to China National Standard (CNS) A4 (210X297 mm)-204 _ 486469 A7 B7 V. Description of the invention (2〇2 ) 114

m/z 570 (M+H) 115m / z 570 (M + H) 115

m/z 544 (M+H)m / z 544 (M + H)

經濟部中央標準局員工消費合作社印製 116 117Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 116 117

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 2〇5 一 m/z 544 (M+H) m/z 594 (M+H) 衣 訂 (請先閲讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（2〇3 ) 118This paper size applies to China National Standard (CNS) A4 (210X297mm) _205 m / z 544 (M + H) m / z 594 (M + H) clothing order (please read the precautions on the back first) (Fill in this page again) 486469 A7 B7 V. Description of the invention (203) 118

ο m/z 578 (M+H) 119ο m / z 578 (M + H) 119

Q m/z 544 (M+H) (請先閱讀背面之注意事項再填寫本頁) 120Q m / z 544 (M + H) (Please read the notes on the back before filling this page) 120

經濟部中央標準局員工消費合作社印製 121Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 121

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本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 2〇6 — m/z 600 (M+H) m/z 600 (M+H) 486469 A7 B7 五、發明説明（2〇4) 122This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm)-206 — m / z 600 (M + H) m / z 600 (M + H) 486469 A7 B7 V. Description of the invention (20) 4) 122

m/z 530 (M+H)m / z 530 (M + H)

123123

m/z 640 (M+H) (請先閲讀背面之注意事項再填寫本頁)m / z 640 (M + H) (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印裝 124 125Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 124 125

m/z 580 (M-fH) 乂m / z 580 (M-fH) 乂

m/z 518 (M+H)m / z 518 (M + H)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 486469 A7 B7 五、發明説明（2〇5 ) 126This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 486469 A7 B7 V. Description of the invention (205) 126

m/z 532 (M+H) 127m / z 532 (M + H) 127

經濟部中央標準局員工消費合作社印製 128 129Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 128 129

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本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 208 _ m/z 564 (M+H) m/z 592 (M+H) m/z 530 (M+H) ---------^^衣-- (請先閱讀背面之注意事項再填寫本頁) 訂 486469 A7 B7 五、發明説明（2〇6 ) 130This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 208 _ m / z 564 (M + H) m / z 592 (M + H) m / z 530 (M + H) --- ------ ^^ 衣-(Please read the notes on the back before filling out this page) Order 486469 A7 B7 V. Description of the invention (206) 130

m/z 606 (M+H)m / z 606 (M + H)

131131

m/z 544 (M+H)m / z 544 (M + H)

132132

m/z 654 (M+H) 經濟部中央標隼局員工消費合作社印製m / z 654 (M + H) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

5H) m/2(M+ o N/ b (請先閱讀背面之注意事項再填寫本頁)5H) m / 2 (M + o N / b (Please read the notes on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 209 - 486469 A7 B7 五、發明説明（2〇7) 134This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 209-486469 A7 B7 V. Description of the invention (207) 134

m/z 615 (M+H)m / z 615 (M + H)

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135135

m/z 544 (M+H)m / z 544 (M + H)

(請先閱讀背面之注意事項再填寫本頁) 136(Please read the notes on the back before filling out this page) 136

m/z 656 (M+H) 137 經濟部中央標準局員工消費合作社印製m / z 656 (M + H) 137 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

m/z 656 (M+H) 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 一 486469 A7 B7 五、發明説明（ 208) 138m / z 656 (M + H) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) _ One 486469 A7 B7 V. Description of the invention (208) 138

m/z 532 (M+H)m / z 532 (M + H)

下列實例中 分離法（方法C 實例139至167 所製化合物係藉製備性高效能液體色層 予以純化，並以三氟乙酸鹽形式離析出 (請先閱讀背面之注意事項再填寫本頁) 139 140 經濟部中央標準局員工消費合作社印製Separation method in the following examples (Method C Examples 139 to 167 The compounds were purified by a preparative high-performance liquid chromatographic layer and isolated as trifluoroacetate (please read the precautions on the back before filling this page). 140 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

m/z 565 (M+H) m/z 593 (M+H) 本紙張尺度適用中國國家標準（CNS)A4規格（21QX 297公釐）_ 486469 A7 B7 五、發明説明（2〇9) 141 142m / z 565 (M + H) m / z 593 (M + H) This paper size is applicable to China National Standard (CNS) A4 (21QX 297 mm) _ 486469 A7 B7 V. Description of the invention (209) 141 142

經濟部中央標準局員工消費合作社印製 143Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 143

m/z 567 (M+H) m/z 551 (M+H) m/z 551 (M+H) (請先閲讀背面之注意事項再填寫本頁) 訂 144m / z 567 (M + H) m / z 551 (M + H) m / z 551 (M + H) (Please read the notes on the back before filling this page) Order 144

m/z 566 (M+H) 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 212 - 486469 A7 B7 五、發明説明（210 ) 145m / z 566 (M + H) This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 1 212-486469 A7 B7 V. Description of the invention (210) 145

m/z 597 (M+H) 146 147m / z 597 (M + H) 146 147

m/z 609 (M+H) m/z565 (M+H) (請先閲讀背面之注意事項再填寫本頁) 148 經濟部中央標準局員工消費合作社印製m / z 609 (M + H) m / z565 (M + H) (Please read the notes on the back before filling out this page) 148 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

m/z 61 6 (M+H) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）— 213 - 486469 A7 B7 五、發明説明（211 ) 149m / z 61 6 (M + H) This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) — 213-486469 A7 B7 V. Description of the invention (211) 149

m/z 61 (M+H) 150m / z 61 (M + H) 150

m/z 601 (M+H) 151m / z 601 (M + H) 151

m/z 601 (M+H) 訂 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 152m / z 601 (M + H) Order (Please read the notes on the back before filling this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 152

0 m/z 552 N (m+h) 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X 297公釐214 一 486469 A7 B7 五、發明説明（212 ) 153 η0 m / z 552 N (m + h) This paper size is applicable to China National Standard (CNS) A4 (210X 297 mm 214 a 486469 A7 B7 V. Description of the invention (212) 153 η

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0 m/z 552 (M+H) Ν, 154 m/z 5670 m / z 552 (M + H) Ν, 154 m / z 567

(請先閱讀背面之注意事項再填寫本頁) 155(Please read the notes on the back before filling out this page) 155

m/z 602 (M+H) 156 經濟部中央標準局員工消費合作社印製m / z 602 (M + H) 156 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

…从 m/z 592ΓΥΛι _N 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）一 215 - 486469… From m / z 592ΓΥΛι _N This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)-215-486469

159159

m/z 613 (M+H) (請先閲讀背面之注意事項再填寫本頁) 160 經濟部中央標準局員工消費合作社印製m / z 613 (M + H) (Please read the precautions on the back before filling out this page) 160 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

m/z 670 (M+NH4) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 216 - 486469 A7 B7 五、發明説明（2H ) 161m / z 670 (M + NH4) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) _ 216-486469 A7 B7 V. Description of invention (2H) 161

m/z 634 (M+H) 162m / z 634 (M + H) 162

m/z 654 (M+H) (請先閲讀背面之注意事項再填寫本頁) 163m / z 654 (M + H) (Please read the notes on the back before filling this page) 163

m/z 650 (M+H)m / z 650 (M + H)

164 經濟部中央標準局員工消費合作社印製164 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

m/z 636 (M+H) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 217 - 486469 A7 B7 五、發明説明（215) 165m / z 636 (M + H) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) _ 217-486469 A7 B7 V. Description of the invention (215) 165

Ο m/z 684 « (M+H) 166Ο m / z 684 «(M + H) 166

m/z 596 (M+H) (請先閱讀背面之注意事項再填寫本頁) 167m / z 596 (M + H) (Please read the notes on the back before filling this page) 167

m/z 557 (M+H)m / z 557 (M + H)

Q v〇 經濟部中央標準局員工消費合作社印裝 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 218 _ 486469Q v〇 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1 218 _ 486469

經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（216) 實例1 β ft 9 —〔4 一〔4 一〔（苯氧羰基）胺基〕一 1 一哌啶基〕 丁基〕一 N —（2，2，2 —三氟乙基）—9H —芴一 9 一甲醯胺，單氫氯酸鹽__ 於0°C下，將氯甲酸苯酯（〇 · 14毫升，1 · 06 毫莫耳）逐滴加至實例3 6第D部胺（5 0 0毫克， 0 · 96毫莫耳）及三乙胺（〇 · 33毫升，2 · 4毫莫 耳）之二氯甲烷（5毫升）溶液中。再將反應加溫至室溫 ，而後連續攪拌1小時。繼而將二氯甲烷（1 〇 〇毫升） 加入，再將溶液以飽和碳酸氫鈉（2 X 3 0毫升），水（ 2x30毫升），鹽水（2x30毫升）清洗及於硫酸鎂 上乾燥。蒸發後可得黃色油狀物。而後藉於矽膠（1 〇 〇 克）上進行急驟色層分離，以5 %甲醇之二氯甲烷液裝填 及洗提而予以純化。再結合純溶離份並蒸發成無色油狀物 。繼而令所得產物溶於甲醇（1毫升）中，再將氫氯酸之 乙醚溶液（1 · 1莫耳濃度，1 · 1毫升）加入。而後將 反應於室溫下攪拌1 0分鐘，再蒸發至乾。繼而將產物於 真空爐乾燥（50 °C，24小時），即得白色固狀之標題 化合物（300毫克，53%)。 熔點· 197-200 °C MS (ES，+ 離子）m/e 5 6 6 ( Μ + Η ) 分析· C32H35Cj2F303· 0 · 6Η2〇 之計算值： C，62.71;H，5.95;N，6.86 ;F，9 · 3 0 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X 297公釐）_ 219 - (請先閲讀背面之注意事項再填寫本頁) 486469 經濟部中央標準局員工消費合作社印製 A7 ____B7 五、發明説明（217) 實測值：C，6 2 · 7 9 ; Η，5 · 8 8 ; N，6 · 5 0 ;F，9 · 1 0 實例1 6 9 9 一〔4 一〔4 一〔〔（苯胺基）鑛基〕胺基〕一 1 一哌 啶基〕丁基〕一 N —（2，2，2 —三氟乙基）一 9H — 荀一 9 一甲醯胺，單氫氯酸鹽__ 於〇°C下，將異氰酸苯酯（〇 · 1〇毫升，；[· 〇6 毫莫耳）逐滴加至實例3 6第D部胺（5 0 0毫克， 0 · 96毫莫耳）及三乙胺（0 · 33毫升，2 · 4毫莫 耳）之二氯甲烷（5毫升）溶液中。再將反應加溫至室溫 ，而後連續攪拌1小時，繼而將二氯甲烷（1 〇 〇毫升） 加入，再將溶液以飽和碳酸氫鈉（2 X 3 0毫升），水（ 2x30毫升），鹽水（2x30毫升）清洗及於硫酸鎂 上乾燥。蒸發後可得黃色油狀物。再藉於矽膠（1 0 0克 )上進行急驟色層分離，以5 %甲醇之二氯甲烷液裝填及 洗提而予以純化。而後結合純溶離份，並予蒸發以得無色 油狀物。令所得產物溶於甲醇（2毫升）中，再將氫氯酸 之乙醚溶液（1 · 1莫耳濃度，1 · 1毫升）加入。而後 將反應於室溫下攪拌1 0分鐘，繼而蒸發至乾。再將產物 於真空爐中乾燥（5 5 °C，2 4小時），即得白色固狀之 標題化合物（200毫克，40%)。 熔點· 1 4 5 — 1 5 0 °C MS (CI ，+離子）565 (M+H) (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X29?公釐） 220 - 486469 A7 B7五、發明説明（218) 分析· C32H36C芡F3N4〇2· 0 · 6 H2〇之計算值： C，62.81;H，6.13;N，9.16Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (216) Example 1 β ft 9 — [4 a [4 a [(phenoxycarbonyl) amino] a 1 piperidinyl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9 monomethylamine, monohydrochloride _ At 0 ° C, phenyl chloroformate (0.14 ml, 1.06 mmol) was added dropwise to the second part of Example 3 6 Part A amines (500 mg, 0.996 mmol) and triethylamine (0.33 ml, 2.4 mmol) Methyl chloride (5 ml) in solution. The reaction was warmed to room temperature and stirred continuously for 1 hour. Dichloromethane (100 ml) was then added, and the solution was washed with saturated sodium bicarbonate (2 x 30 ml), water (2 x 30 ml), brine (2 x 30 ml) and dried over magnesium sulfate. A yellow oil was obtained after evaporation. It was then purified by flash chromatography on silica gel (1000 g), filling with 5% methanol in dichloromethane and elution. Combine the pure fractions and evaporate to a colorless oil. The resulting product was then dissolved in methanol (1 ml), and a solution of hydrochloric acid in ether (1.1 mol concentration, 1.1 ml) was added. The reaction was then stirred at room temperature for 10 minutes and evaporated to dryness. The product was then dried in a vacuum oven (50 ° C, 24 hours) to obtain the title compound (300 mg, 53%) as a white solid. Melting point · 197-200 ° C MS (ES, + ion) m / e 5 6 6 (Μ + Η) analysis · C32H35Cj2F303 · Calculated value of 0 · 6Η20: C, 62.71; H, 5.95; N, 6.86; F , 9 · 3 0 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297mm) _ 219-(Please read the precautions on the back before filling this page) 486469 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7 V. Description of the invention (217) Measured value: C, 6 2 · 7 9; Η, 5 · 8 8; N, 6 · 5 0; F, 9 · 1 0 Example 1 6 9 9 one [4 one [ 4 [[((aniline) mineral] amino] amino] -1 1 piperidinyl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-methaneamine, Monohydrochloride__ At 0 ° C, phenyl isocyanate (0.10 ml,; [· 〇6 mmol) was added dropwise to Example 36 Part D amine (50 0 0 Mg, 0. 96 mmol) and triethylamine (0.33 ml, 2.4 mmol) in dichloromethane (5 ml). The reaction was further warmed to room temperature, and then continuously stirred for 1 hour, then dichloromethane (100 ml) was added, and the solution was saturated sodium bicarbonate (2 x 30 ml), water (2 x 30 ml), Wash with brine (2x30 mL) and dry over magnesium sulfate. A yellow oil was obtained after evaporation. Then it was purified by flash chromatography on silica gel (100 g), and then filled with 5% methanol in dichloromethane. Then, the pure soluble fractions were combined and pre-evaporated to obtain a colorless oil. The resulting product was dissolved in methanol (2 ml), and a solution of hydrochloric acid in diethyl ether (1.1 mol concentration, 1.1 ml) was added. The reaction was then stirred at room temperature for 10 minutes and then evaporated to dryness. The product was dried in a vacuum oven (55 ° C, 24 hours) to obtain the title compound (200 mg, 40%) as a white solid. Melting point · 1 4 5 — 1 5 0 ° C MS (CI, + ion) 565 (M + H) (Please read the precautions on the back before filling out this page) The paper size applies to Chinese National Standard (CNS) A4 specifications ( 210X29? Mm) 220-486469 A7 B7 V. Description of the invention (218) Analysis · C32H36C 芡 F3N4〇2 · 0 · 6 H2〇 Calculated values: C, 62.81; H, 6.13; N, 9.16

FF

IX C 值 測 實 Η οIX C value measured Η ο

F 7 ο 7 1± 例 實 C 2 鹽 I , 酸 4 2 氯 c C 氫 I I 單 4 Ν ， C I 胺1 ] S 9 基甲 基基 胺乙 } 氟 醯三 磺 I 苯 2 基 I 啶芴 哌 I I Η 1 9 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於0 °C下，將苯磺醯氯（〇 · 13毫升，1 · 〇6毫 莫耳）逐滴加至實例3 6第D部胺（5 〇 〇毫克， 0 · 96毫莫耳）及三乙胺（〇 · 46毫升，3 · 36毫 莫耳）之二氯甲烷（5毫升）溶液中。再將反應加溫至室 溫，並連續攪拌1小時。而後將二氯甲烷（1 〇 〇毫升） 加入，再將溶液以飽和碳酸氫鈉（2 X 3 0毫升），水（ 2x30毫升）’鹽水（2x30毫升）清洗及於硫酸鎂 上乾燥。蒸發後可得黃色油狀物。再藉於矽膠（1 〇 〇克 )上進行急驟色層分離，以5 %甲醇之二氯甲烷液裝填及 洗提而予以純化’繼而結合純溶離份，並予蒸發以得無色 油狀物。令所得產物溶於甲醇（2毫升）中，再將氫氯酸 之乙醚溶液（1·1莫耳濃度，1·1毫升）加入。而後 將反應於室溫下攪拌1 0分鐘，繼而蒸發至乾。再將產物 於真空爐中乾燥（55 °C，24小時），即得白色固狀之 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 486469 A7 B7五、發明説明（219) 標題化合物（400毫克，71%)。 熔點· 1 3 0 - 1 3 4 °C“3(£3，+離子）：586 (“ + 11)分析· C31H35C5F3N3S〇3· 0 · 8H2〇之計算值 ： C，58.59;H，5*65;N，6-61;C 义，5.58;F，8.97 實測值：C，5 8 · 7 7 ; Η，5 · 6 6 ; N，6 · 4 0 ;C 芡，5.95;F，9.03。 (請先閲讀背面之注意事項再填寫本頁)F 7 ο 7 1 ± Examples of C 2 Salt I, Acid 4 2 Chlorine C C Hydrogen II Mono 4 Ν, CI Amine 1] S 9 Methylmethylaminoamine B} Fluorotrisulfonyl I Benzene 2 I I Trimethoprim II Η 1 9 (Please read the notes on the back before filling out this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed at 0 ° C the benzylsulfonyl chloride (0.13 ml, 1.06 mmol) Ear) was added dropwise to Example 36, Part D amines (500 mg, 0.96 mmol) and triethylamine (0.46 ml, 3.36 mmol) in dichloromethane (5 ml). ) In solution. The reaction was warmed to room temperature and stirred continuously for 1 hour. Dichloromethane (100 ml) was then added, and the solution was washed with saturated sodium bicarbonate (2 x 30 ml), water (2 x 30 ml) 'brine (2 x 30 ml) and dried over magnesium sulfate. A yellow oil was obtained after evaporation. It was then purified by flash chromatography on silica gel (1000 g), and purified by filling with 5% methanol in dichloromethane and eluting, and then combined with the pure fractions, and evaporated to obtain a colorless oil. The obtained product was dissolved in methanol (2 ml), and a solution of hydrochloric acid in diethyl ether (1.1 mol concentration, 1.1 ml) was added. The reaction was then stirred at room temperature for 10 minutes and then evaporated to dryness. The product was dried in a vacuum oven (55 ° C, 24 hours) to obtain a white solid paper. The paper size was in accordance with Chinese National Standard (CNS) A4 specification (210X297 mm) 486469 A7 B7 V. Description of the invention (219) Title compound (400 mg, 71%). Melting point · 1 3 0-1 3 4 ° C "3 (£ 3, + ions): 586 (" + 11) analysis · Calculated for C31H35C5F3N3S〇3 · 0 · 8H2〇: C, 58.59; H, 5 * 65 N, 6-61; C meaning, 5.58; F, 8.97 found: C, 5 8 · 7 7; Η, 5 · 6 6; N, 6 · 4 0; C 芡, 5.95; F, 9.03. (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 A. 實例1 7 1Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A. Example 1 7 1

於氬下（抽空及以氬淨化三次），於一 10 °c下’將 4 · 0毫升正丁基鋰（10 · 0毫莫耳，2 · 5莫耳濃度 之己烷液）於1 0分鐘期間加至1 · 〇 5克（5 · 0 0毫 本紙張尺度適用中國國家標準（CNS)A4-%格（210X 297公釐）_ mg 486469 經濟部中央標準局員工消費合作社印製 A7 ____B7____五、發明説明（220) 莫耳）9 -芴羧酸之1 5毫升四氫呋喃溶液中。最初形成 稠厚漿液，繼而爲黃色溶液。30分鐘後，將0 · 75毫 升（7 · 0毫莫耳）溴丁酸乙酯加入。再令反應加溫至室 溫。2 4小時後，使用1 0 %檸檬酸溶液令反應中止，再 以乙酸乙酯萃取兩次。繼而將有機萃取液乾燥（硫酸鈉） 及蒸發。令餘留物溶於1 5毫升二氯甲烷中，再於室溫下 ，於氬下攪拌，同時將7 · 5毫升草醯氯溶液（2莫耳濃 度之二氯甲烷液，15毫莫耳），繼而將二甲基甲醯胺（ 1 0 0微升）加入。1小時後，將所得溶液於低於3 0 °C 之溫度下蒸發，而後令之再溶於1 5毫升四氫呋喃中。繼 而將此溶液於氬下，於0°C下加至2，2，2 -三氟乙胺 (1·1克，11毫莫耳）之10毫升四氫呋喃溶液中。 1小時後，使用1 0%檸檬酸溶液令反應中止，再以乙酸 乙酯萃取兩次。繼而將萃取液結合，乾燥（硫酸鎂）及蒸 發。再藉於矽膠上進行急驟色層分離（5 X 1 5公分柱， 3 : 9 7乙醚/二氯甲烷作爲洗提液）而予以純化，即得 白色固狀之標題化合物，9 56毫克，47%產率，熔點 • 108 - 110 〇C。 B. (請先閱讀背面之注意事項再填寫本頁)Under argon (evacuated and purged with argon three times), at a temperature of 10 ° C, 4.0 ml of n-butyllithium (10.0 mmol, 2.5 mmol of hexane) was added to 10 Add to 1.05 grams (5.0 milligrams of paper in minutes) Applicable to China National Standard (CNS) A4-% (210X 297 mm) _ mg 486469 Printed by A7, Consumer Cooperative of Central Standards Bureau, Ministry of Economic Affairs __B7___ V. Description of the invention (220) Moore) 9-fluorenecarboxylic acid in 15 ml of tetrahydrofuran solution. A thick slurry formed initially, followed by a yellow solution. After 30 minutes, 0.75 milliliters (7.0 millimoles) of ethyl bromobutyrate was added. The reaction was warmed to room temperature. After 24 hours, the reaction was stopped with 10% citric acid solution, and extracted twice with ethyl acetate. The organic extract was then dried (sodium sulfate) and evaporated. The residue was dissolved in 15 ml of dichloromethane, and then stirred at room temperature under argon. At the same time, 7.5 ml of chloramphenicol solution (2 moles of dichloromethane solution, 15 millimoles) ), Then add dimethylformamide (100 microliters). After 1 hour, the resulting solution was evaporated at a temperature below 30 ° C and then redissolved in 15 ml of tetrahydrofuran. This solution was then added to a solution of 2,2,2-trifluoroethylamine (1.1 g, 11 mmol) in 10 ml of tetrahydrofuran at 0 ° C under argon. After 1 hour, the reaction was stopped with a 10% citric acid solution and extracted twice with ethyl acetate. The extracts were combined, dried (magnesium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (5 X 1 5 cm column, 3: 9 7 ether / dichloromethane as eluent) and purified to obtain the title compound as a white solid, 9 56 mg, 47 % Yield, melting point • 108-110 ° C. B. (Please read the notes on the back before filling this page)

於室溫下，於氬下’將氫氧化鋰水合物（1 3 0毫克 本紙張尺度適用中國國家標準（(：阳）八4規格（210><297公釐）-223 : 應~ 486469 A7 ___B7五、發明説明（221) ’ 3 · 0毫莫耳）之5毫升水溶液加至第A部化合物（ 580毫克，1·43毫莫耳）之5毫升甲醇溶液中。再 將反應混合物攪拌1 4小時，而後部分蒸發以移去甲醇。 繼而使用1 0 %檸檬酸令反應中止，再以乙酸乙酯萃取兩 次。而後結合萃取液’並予乾燥（硫酸鎂）及蒸發，即得 白色固狀之標題化合物（540毫克）。彼乃用於下一步 驟中而不必更進一步純化。 c.At room temperature, under argon, the lithium hydroxide hydrate (130 mg of this paper applies the Chinese national standard ((: yang) 8 4 specifications (210 > < 297 mm) -223: should ~ 486469 A7 ___B7 V. Description of the invention (221) '3.0 mmoles) 5 ml of aqueous solution was added to a 5 ml methanol solution of the compound of Part A (580 mg, 1.43 mmoles). The reaction mixture was stirred 14 hours, and then partially evaporated to remove methanol. Then the reaction was stopped with 10% citric acid and extracted twice with ethyl acetate. Then the extracts were combined and dried (magnesium sulfate) and evaporated to give a white color. The title compound was solid (540 mg). It was used in the next step without further purification. C.

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 於室溫下，於氬下，將二環己基碳化二亞胺（2 9 5 毫克，1 · 43毫莫耳）加至第B部化合物（ 5 30毫克 ，1 · 41毫莫耳），實例10第B部胺（280毫克， 1 · 41毫莫耳）及HOAt (210毫克· 1，5毫莫 耳）之5毫升四氫呋喃溶液中。15小時後，使用10% 檸檬酸令反應中止，再以乙酸乙酯萃取兩次。而後將萃取 液結合，以水清洗一次，以飽和碳酸氫鈉溶液清洗一次， 並予乾燥（硫酸鈉）及蒸發。再藉於矽膠上進行急驟色層 分離（5x1 5公分柱，1 : 2乙酸乙酯/二氯甲烷作爲 洗提液）而予以純化，即得白色固狀之標題化合物（ 625毫克，79%產率），熔點90 - 92 °C。 本紙張尺度適用中國國家標準（ CNS ) A4規格（210X297公釐）_ 224 __ 486469 經濟部中央標準局員工消費合作社印製 A7 ____B7五、發明説明（222) 分析· C30H36F 3Ν3〇4· H2〇之計算值： C，62*38;H，6.63;F，9.87 ;N，7 · 2 7 實測值：C，6 2 · 4 1 ; Η，6 · 2 4 ; F，9 · 7 8 ;Ν，7 · 1 4。 MS (電噴霧，一離子）m/e 558 (Μ — Η)。 實例1 7 ?· 順式—9 一〔4 —〔4 一〔（2 -苯氧基苯醯）胺基〕一 1 一哌啶基〕丁基〕一 Ν -（2，2，2 -三氟乙基）一 —9_ Η —荀一 9 一甲醯胺，Ν —氧化物__ 於〇°C下，於氬下，將3 —氯基過苯甲酸（8 0 — 85%) (82毫克，0.407毫莫耳）之二氯甲烷（ 1 · 5毫升）溶液於5分鐘期間徐緩加至實例3 2游離胺 (290毫克，〇 · 452毫莫耳）之二氯甲烷（5毫升 )溶液中。再將反應混合物於〇°C下攪拌1 〇分鐘，而後 將飽和水性碳酸氫鈉（1毫升）加入。繼而將反應混合物 於0 °C下強烈攪拌1小時，以二氯甲烷（1 〇毫升）稀釋 ’以鹽水（5毫升）清洗，繼而於硫酸鈉上乾燥。蒸發後 可得3 2 0毫克白色泡沬狀物，再將其藉於矽膠（5 〇克 )上進行急驟色層分離並以3%至5%甲醇/二氯甲烷梯 度洗提而予以純化，即得白色泡沬固狀之標題化合物（ 7 4 毫克，2 5 % )。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） -225 - 486469 經濟部中央標準局員工消費合作社印製 A7 __B7五、發明説明（ 223) MS (ES，+ 離子）m/z 658 (M + H) 分析· C38H38F3N3〇4+H2〇之計算值： C，67.54;H，5.97;N，6.22 ;F，8 · 4 3 實測值：C，6 7 · 6 1 ; Η，5 · 6 5 ; N，6 · 1 8 ;F，8 · 2 1 ° 實例1 7 3 9 一〔 4 一〔 4 一〔（ 2 -苯氧基苯醯）胺基〕一 1 一哌 啶基〕一 4 一合氧基丁基〕—Ν — (2，2，2 —三氟乙 基）一 9Η -芴一9 —甲醯胺_____ 將實例171化合物（2 · 〇〇克，3 . 59毫莫耳 )之1 0毫升4當量濃度氫氯酸之二噁烷溶液攪拌（以氯 化鈣乾燥管保護）3小時。再將溶液於3 0 °C下蒸發，而 後令所得固狀物再溶於1 0毫升二氯甲烷中。繼而將三乙 胺（0·75毫升，5，4毫莫耳），而後將500毫克 2 —苯氧基苯醯氯（2 · 1 5毫莫耳）於1 0分鐘期間加 至已於氬下冷卻至一 1 0°C之一半重量之此溶液中。1小 時後，使用飽和碳酸氫鈉溶液令反應中止，再以乙酸乙酯 萃取兩次。而後將有機萃取液乾燥（硫酸鈉）及蒸發。再 藉於矽膠上進行急驟色層分離（5x15公分柱，1 : 9 己烷/乙酸乙酯作爲洗提.液）而予以純化，由乙酸乙酯/ 己烷中再結晶後，即得白色固狀之標題化合物（7 4 5毫 克，63%產率），熔點96-98乇。 本紙張尺度適用中ί國家標準（CNS ) A4規格（210 X 297公釐）_ 226 _ (請先閱讀背面之注意事項再填寫本頁) 486469 A7 _____ B7_ 五、發明説明（224) 分析· C38H36F3N304+H2〇之計算值： C，67.74;H，5.69;F，8.46 ;N，6 · 2 4 實測值：C，6 7 · 8 4 ; Η，5 · 6 1 ; F，8 · 6 3 ;Ν，6 · 0 0。 MS (電噴霧，+ 離子）m/z 65 6· 3 (M + H) ，673·3(Μ + ΝΗ4)〇 (請先閱讀背面之注意事項再填寫本頁) 實例1 7 4(Please read the notes on the back before filling this page.) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed it at room temperature and under argon, dicyclohexylcarbodiimide (2.55 mg, 1.43 mmol) Mol) to the compound of Part B (530 mg, 1.41 mmol), Example 10 Part B amine (280 mg, 1.41 mmol) and HOAt (210 mg, 1.5 mmol) Ear) in 5 ml of tetrahydrofuran solution. After 15 hours, the reaction was quenched with 10% citric acid and extracted twice with ethyl acetate. The extracts were then combined, washed once with water, once with a saturated sodium bicarbonate solution, and dried (sodium sulfate) and evaporated. It was then purified by flash chromatography on silica gel (5x1 5 cm column, 1: 2 ethyl acetate / dichloromethane as eluent) and purified to obtain the title compound (625 mg, 79% yield) as a white solid. Ratio), melting point 90-92 ° C. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 224 __ 486469 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____B7 V. Description of the invention (222) Analysis · C30H36F 3Ν3 04 · H2〇 Calculated: C, 62 * 38; H, 6.63; F, 9.87; N, 7 · 2 7 Found: C, 6 2 · 4 1; Η, 6 · 2 4; F, 9 · 7 8; Ν, 7 · 1 4. MS (electrospray, one ion) m / e 558 (M — Η). Example 1 7? · Cis-9-9 [4- [4-[(2-phenoxyphenylhydrazone) amino] -1 1-piperidinyl] butyl] -N-(2,2,2 -tri Fluoroethyl)-9_fluorene-fluorene-9-methylamine, N-oxide__ at 0 ° C, under argon, 3-chloroperbenzoic acid (80-85%) (82 Milligram, 0.407 millimoles) of dichloromethane (1.5 milliliters) was slowly added over 5 minutes to Example 32 2 solution of free amine (290 milligrams, 0.452 millimoles) in dichloromethane (5 milliliters) in. The reaction mixture was stirred at 0 ° C for 10 minutes, and then saturated aqueous sodium bicarbonate (1 ml) was added. The reaction mixture was then vigorously stirred at 0 ° C for 1 hour, diluted with dichloromethane (10 ml), washed with brine (5 ml), and then dried over sodium sulfate. After evaporation, 320 mg of white foam can be obtained, which is then purified by flash chromatography on silica gel (50 g) and eluted with a gradient of 3% to 5% methanol / dichloromethane. The title compound was obtained as a white foam (74 mg, 25%). (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) -225-486469 Printed by A7 __B7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Explanation (223) MS (ES, + ion) m / z 658 (M + H) analysis · Calculated value for C38H38F3N3〇4 + H2〇: C, 67.54; H, 5.97; N, 6.22; F, 8 · 4 3 Measured value: C, 6 7 · 6 1; Η, 5 · 6 5; N, 6 · 1 8; F, 8 · 2 1 ° Example 1 7 3 9 1 [4 1 [4 1 [(2 -phenoxy Phenyl fluorene) amine]-1-piperidinyl]-4-oxybutyl] -N-(2,2,2-trifluoroethyl)-9Η-芴 9-formamidine _____ 10 ml of a solution of the compound of Example 171 (2.0 g, 3.59 mmol) in 4 equivalents of hydrochloric acid in dioxane was stirred (protected with a calcium chloride drying tube) for 3 hours. The solution was evaporated at 30 ° C, and the resulting solid was redissolved in 10 ml of dichloromethane. Then triethylamine (0.75 ml, 5, 4 mmol) was added, and then 500 mg of 2-phenoxyphenylhydrazone chloride (2.15 mmol) were added to the argon over 10 minutes. Cool down to one and a half weight of this solution at 10 ° C. After 1 hour, the reaction was stopped with a saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was then dried (sodium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (5x15 cm column, 1: 9 hexane / ethyl acetate as the eluent) and purified. After recrystallization from ethyl acetate / hexane, a white solid was obtained. The title compound (75 mg, 63% yield), m.p. 96-98%. This paper is applicable to the National Standard (CNS) A4 specification (210 X 297 mm) _ 226 _ (Please read the precautions on the back before filling this page) 486469 A7 _____ B7_ V. Description of the Invention (224) Analysis · C38H36F3N304 + H2〇 Calculated: C, 67.74; H, 5.69; F, 8.46; N, 6 · 2 4 Found: C, 6 7 · 8 4; H, 5 · 6 1; F, 8 · 6 3; Ν, 6 · 0 0. MS (electrospray, + ion) m / z 65 6.3 (M + H), 673.3 (M + ΝΗ4) 〇 (Please read the precautions on the back before filling this page) Example 1 7 4

經濟部中央標準局員工消費合作社印製 將實例171化合物（2 · 00克，3 · 59毫莫耳 )之1 0毫升4當量濃度氫氯酸之二噁烷溶液攪拌（以氯 化鈣乾燥管保護）3小時。再將溶液於3 0 °C下蒸發，而 後令所得固狀物再溶於1 0毫升二氯甲烷中。繼而將三乙 胺（0 · 75毫升，5 · 4毫莫耳），而後將0 · 25毫 升苯醯氯（2 · 2毫莫耳）於1 0分鐘期間加至已於氬下 冷卻至一 1 0°C之一半重量之此溶液中。1小時後，使用 飽和碳酸氫鈉溶液令反應中止，再以乙酸乙酯萃取兩次。 而後將有機萃取液乾燥（硫酸鈉）及蒸發。再藉於矽膠上 227 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公釐） 486469 A7 B7 五、發明説明（225 ) 進行急驟色層分離（5> XI 5公分柱，1 : 9己烷/乙酸 乙酯作爲洗提液）而予以純化，由乙酸乙酯/己烷中再結 晶後，即得白色固狀之標題化合物（725毫克，71% 產率），熔點204 — 206 °C。 分析· C32H32F3N303之計算值： <：，68·19;Η，5·7 2; F，l〇-ll;N，7-46 實測值：C，6 8 · 1 4 ; Η，5 · 7 3 ; F，10-33;N，7-40° MS (電噴霧，一離子）m/z 437 (m-cf3ch2nhc〇）， 5 6 2 ( Μ — Η )。 實例1 7 5 9 —〔4 一〔4 一〔〔 （1 ，1 一二甲基乙氧基）羰基〕 胺基〕—1—呢π定基〕戊基〕一 N— (2，2，2 —三氣 乙基）一9H —芴一9 —甲醯胺__Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, stirring 10 ml of a 4-equivalent solution of hydrochloric acid in dioxane (Example 171 compound (2.00 g, 3.59 mmol)) (drying the tube with calcium chloride) Protection) 3 hours. The solution was evaporated at 30 ° C, and the resulting solid was redissolved in 10 ml of dichloromethane. Then triethylamine (0.75 ml, 5.4 mmol) was added, and 0.25 ml phenylhydrazone (2.2 mmol) was added over a period of 10 minutes until it had been cooled to one under argon. One half of this solution at 10 ° C. After 1 hour, the reaction was quenched with a saturated sodium bicarbonate solution and extracted twice with ethyl acetate. The organic extract was then dried (sodium sulfate) and evaporated. Then borrow 227 on the silicone. This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 486469 A7 B7 V. Description of the invention (225) Performing a rapid color layer separation (5 > XI 5 cm column, 1 : 9 hexane / ethyl acetate was used as the eluent) and purified. After recrystallization from ethyl acetate / hexane, the title compound (725 mg, 71% yield) was obtained as a white solid, m.p. 204 — 206 ° C. Analysis · Calculated value of C32H32F3N303: <:, 68 · 19; Η, 5.7 2; F, 10-ll; N, 7-46 Measured value: C, 6 8 · 1 4; Η, 5 · 7 3; F, 10-33; N, 7-40 ° MS (electrospray, single ion) m / z 437 (m-cf3ch2nhc0), 5 6 2 (M — Η). Example 1 7 5 9 — [4— [4 — [[(1,1—Dimethylethoxy) carbonyl] amino]] — 1—N—pyridyl] pentyl] —N— (2, 2, 2 —Trifluoroethyl) —9H —fluorene-9—methaneamine__

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 於氬下（抽空並以氬淨化三次），於一 10 °C下，將 10 · 0毫升正丁基鋰（25 · 0毫莫耳，2 · 5莫耳濃 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）—228 _ 486469 A7 ___B7__ 五、發明説明（226 ) 度之己烷液）於10分鐘期間加至2 · 50克（11 · 9 毫莫耳）9-芴羧酸之25毫升四氫呋喃溶液中。最初形 成稠厚漿液，繼而爲黃色溶液。40分鐘後，將2·05 毫升（15 · 0毫莫耳）1，4 一二溴戊烷加入。再令反 應加溫至室溫。6 0小時後，使用1 0 %檸檬酸溶液令反 應中止，再以乙酸乙酯萃取兩次。繼而將有機萃取液乾燥 (硫酸鎂）及蒸發。再將餘留物於乙酸乙酯/己烷中碾磨 ，即得白色固狀之標題化合物（3 · 7 2克，8 7 % )。 B · (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Under argon (evacuate and purify with argon three times), at a temperature of 10 ° C, 10 ml Lithium (25.0 millimoles, 2.5 moles) This paper is sized to the Chinese National Standard (CNS) A4 (21.0X297 mm) —228 _ 486469 A7 ___B7__ 5. Explanation of the invention (226) degrees of hexane Solution) was added to a solution of 2.50 g (11.9 mmol) of 9-fluorenecarboxylic acid in 25 ml of tetrahydrofuran over a period of 10 minutes. A thick slurry formed initially, followed by a yellow solution. After 40 minutes, 2.05 ml (15.0 mmol) of 1,4-dibromopentane was added. Allow the reaction to warm to room temperature. After 60 hours, the reaction was stopped with a 10% citric acid solution and extracted twice with ethyl acetate. The organic extract was then dried (magnesium sulfate) and evaporated. The residue was triturated in ethyl acetate / hexane to obtain the title compound (3.72 g, 87%) as a white solid. B · (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 於室溫下，於氬下，將0·65毫升草醯氯（7·5 毫莫耳）及二甲基甲醯胺（1 0 0微升）先後加至已攪拌 之1 · 80克（約5 · 0毫莫耳）第A部化合物之1〇毫 升二氯甲烷溶液中。1小時後，將所得溶液於低於3 0 °C 之溫度下蒸發，而後令餘留物再溶於1 5毫升二氯甲烷中 。繼而於氬下，於0°C下，將此溶液加至2，2，2 —三 氟乙胺氫氯酸鹽（820毫克，6 · 0毫莫耳）及2 · 1 毫升三乙胺（1 5毫莫耳）之2 0毫升二氯甲烷溶液中。 1小時後，使用1 0%擰檬酸溶液令反應中止並以乙酸乙 酯萃取兩次。再將萃取液結合，乾燥（硫酸鎂）及蒸發。 令粗製產物溶於2 5毫升2 — 丁酮中，再將7 · 7克（ 本紙張尺度適用中國國家標準（CNS ) Α4規格（ 210X297公釐）二229 - " 486469 A7 ._______B7五、發明説明（227) 5 2毫莫耳）碘化鈉加入，而後令反應混合物於氬下迴流 4 8小時，再將溶液冷卻，蒸發，令產物分界於乙酸乙酯 及1 0%亞硫酸氫鈉溶液間。繼而將有機萃取液（硫酸鎂 )及蒸發。再藉於矽膠上進行急驟色層分離（5 X 1 5公 分柱，3 : 7己烷/二氯甲烷作爲洗提液），而予以純化 ’即得白色固狀之標題化合物（1 · 4 2克，58%產率 )，熔點 102 - 106 °C。 C.The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed at room temperature, under argon, 0.565 ml of chloramphenicol (7.5 mmol) and dimethylformamide (100 microliters) in that order. Add to a stirred solution of 1.80 g (about 5.0 mmol) of Part A compound in 10 ml of dichloromethane. After 1 hour, the resulting solution was evaporated at a temperature below 30 ° C, and the residue was redissolved in 15 ml of dichloromethane. This solution was then added to 2,2,2-trifluoroethylamine hydrochloride (820 mg, 6.0 mmol) and 2.1 ml of triethylamine (at 0 ° C) under argon. 15 mmol) in 20 ml of dichloromethane. After 1 hour, the reaction was stopped with 10% citric acid solution and extracted twice with ethyl acetate. The extracts were combined, dried (magnesium sulfate) and evaporated. The crude product was dissolved in 25 ml of 2-butanone, and then 7.7 g (this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 2229-& 486469 A7. _______ B7 V. Invention Note (227) 5 2 mmol. Sodium iodide was added, and then the reaction mixture was refluxed under argon for 4 8 hours. The solution was cooled and evaporated, and the product was delimited by ethyl acetate and 10% sodium bisulfite solution. between. The organic extract (magnesium sulfate) was then evaporated. Then it was purified by flash chromatography on a silica gel (5 X 1 5 cm column, 3: 7 hexane / dichloromethane as eluent), and purified to obtain the title compound as a white solid (1 · 4 2 G, 58% yield), melting point 102-106 ° C. C.

經濟部中央標隼局員工消費合作社印製Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

(請先閲讀背面之注意事項再填寫本頁) 將第B部化合物（1 · 27克，2 · 60毫莫耳）， 實例10第B部胺（680毫克，3 · 38毫莫耳）及碳 酸鉀（420毫克，3 · 0毫莫耳）之5毫升二甲基甲醯 胺溶液於室溫下，於氬下加熱至50 °C，15小時後，使 用水令反應中止，潷析，再將油.狀餘留物以乙酸乙酯萃取 兩次。繼而將萃取液結合，以水清洗一次，以飽和碳酸氫 鈉溶液清洗一次，並予乾燥（硫酸鈉）及蒸發。再藉於砂 膠上進行急驟色層分離法（5x1 5公分柱，1 : 99甲 醇/乙酸乙酯作爲洗提液）而予以純化，即得白色固狀之 標題化合物（1· 20克，82%產率），熔點58 -6 0 〇C。 本紙張I度適用中國國家標準（CNS ) A4規格（210X297公釐）—230 - 486469 A7 B7 五、發明説明（228 ) (請先閲讀背面之注意事項再填寫本頁) 分析· C31H4OF3N3O3+0 · 25H2 ◦之計算值： C，66.00;H，7.24; F，10.18;N，7.45 實測值：C，6 6 · Ο Ο ; Η，7 · 1 4 ; F，10_39;N，7.60° MS (電噴霧，+ 離子）m/e 56 0· 3 (M + H) 〇 實例1 7 fi 9 -〔4 一〔4 -〔〔（2 -苯氧基苯基）磺醯〕胺基〕 一 1 一哌啶基〕丁基一 N— (2，2，2-三氟乙基）— 义Η -芴-9 一甲醯胺單氫氯酸鹽___ 經濟部中央標準局員工消費合作社印製 於—10 °C下，將亞硝酸鈉（2 · 01克，29 · 2 毫莫耳）之水（3 · 5毫升）溶液以不使反應溫度超過 一 5 °C之速率下逐滴加至2 —苯氧基苯胺（5 · 0克， 27 · 0毫莫耳）之濃氫氯酸（20毫升）溶液中。再將 反應於- 5 °C下攪拌1小時，當重氮化作用完全之時，令 二氧化硫起泡通過冰醋酸（1 5毫升）中直至其飽和爲止 。而後將氯化亞銅（0 · 75克）加入，再將二氧化硫連 續置入直至黃橘色懸浮液變爲藍一綠爲止（30分鐘）。 繼而將混合物冷卻至1 0°C，而後將含重氮鹽之溶液於 1 5分鐘期間逐滴加入。將綠色反應混合物加溫至室溫， 再攪拌另30分鐘，繼而倒至冰水（300毫升）中。再 將乙醚（2 0 0毫升）加入，而後將有機層以水（2 X 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 231 - 486469 A7 ____B7___ 五、發明説明（229 ) 100毫升），飽和碳酸氫鈉溶液（6X100毫升）， 鹽水（2 X 1 0 0毫升）清洗及於硫酸鎂上乾燥。蒸發後 可得棕色油狀之含下列結構(Please read the precautions on the back before filling out this page.) Part B compound (1.27 g, 2.60 mmol), Example 10 Part B amine (680 mg, 3.38 mmol) and A solution of potassium carbonate (420 mg, 3.0 mmol) in 5 ml of dimethylformamide was heated to 50 ° C under argon at room temperature. After 15 hours, the reaction was stopped with water and decanted. The oily residue was extracted twice with ethyl acetate. The extracts were combined, washed once with water, once with saturated sodium bicarbonate solution, dried (sodium sulfate) and evaporated. It was then purified by flash chromatography (5x1 5 cm column, 1:99 methanol / ethyl acetate as eluent) on sand gel to obtain the title compound (1.20 g, 82 % Yield), melting point 58-60 ° C. This paper is suitable for Chinese National Standard (CNS) A4 (210X297 mm) —230-486469 A7 B7. 5. Description of the invention (228) (Please read the precautions on the back before filling this page) Analysis · C31H4OF3N3O3 + 0 · 25H2 ◦ Calculated: C, 66.00; H, 7.24; F, 10.18; N, 7.45 Found: C, 6 6 · Ο Ο; Η, 7 · 1 4; F, 10_39; N, 7.60 ° MS (electrical Spray, + ion) m / e 56 0 · 3 (M + H) 〇 Example 1 7 fi 9-[4-[4-[[(2-phenoxyphenyl) sulfonyl]] amino]-1-1 Piperidinyl] butyl-N— (2,2,2-trifluoroethyl) — stilbene-芴 -9 monomethylamine monohydrochloride ___ printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs At -10 ° C, add a solution of sodium nitrite (2.01 g, 29 · 2 mmol) in water (3.5 ml) dropwise to 2 at a rate such that the reaction temperature does not exceed -5 ° C. —Phenoxyaniline (5.0 g, 27.0 mmol) in concentrated hydrochloric acid (20 ml). The reaction was stirred at -5 ° C for 1 hour. When the diazotization was complete, the sulfur dioxide was bubbled through glacial acetic acid (15 ml) until it was saturated. Then cuprous chloride (0.75 g) was added, and sulfur dioxide was continuously added until the yellow-orange suspension became blue-green (30 minutes). The mixture was then cooled to 10 ° C and the diazonium salt-containing solution was added dropwise over a period of 15 minutes. The green reaction mixture was warmed to room temperature, stirred for another 30 minutes, and then poured into ice water (300 ml). Add diethyl ether (200 ml), and then add the organic layer to water (2 X this paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm)-231-486469 A7 ____B7___ V. Description of the invention (229) 100 ml), saturated sodium bicarbonate solution (6 × 100 ml), brine (2 × 100 ml), washed and dried over magnesium sulfate. After evaporation, a brown oil containing the following structure is obtained

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

9 I !9 I!

0 I0 I

I 之混合物（2 · 5克，3 6 % )。 遵循實例480之步驟，令上示磺醯氯（2 · 5克， 9 · 3毫莫耳）與實例36第D部胺（0 · 62克， 1 · 2毫莫耳）起反應，繼而以氫氯酸處理，即得白色固 狀之標題化合物（2 10毫克，26%)。 熔點· 142 - 146 °C MS (ES，+ 離子）·· 678 (M + H) 分析· C37H39C5F3N3SO4+0 · 4H20 之計算值 : (：，61·60;Η，5·56;Ν，5·8 2 經濟部中央標準局員工消費合作社印製 ;Ci?，4-91;S，4-44; F，7 · 9 0 實測值：C，6 1·67;Η，5·55;Ν，5·&2 ;C^，4.66;S，4.31; F，7 · 9 5 ο 實例ΐ 7 7 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）一 232 - 486469 Α7 Β7 五、發明説明（ 230 ) 〔1 一〔 〔2 —〔9一〔 〔 （2，2，2 —三氟乙基）胺 基）羰基〕一 9Η —芴一 9 一基〕乙基〕胺基〕羰基〕一 生一呃啶基1胺某甲酸，1，1 一二甲基乙酯 Α·I mixture (2.5 g, 36%). Following the procedure of Example 480, the above-mentioned sulfonylurea chloride (2.5 grams, 9.3 millimoles) was reacted with the amine of Part D of Example 36 (0.62 grams, 1.2 millimoles), followed by Treatment with hydrochloric acid gave the title compound (2 10 mg, 26%) as a white solid. Melting point · 142-146 ° C MS (ES, + ion) · 678 (M + H) analysis · Calculated values for C37H39C5F3N3SO4 + 0 · 4H20: (:, 61 · 60; Η, 5.56; Ν, 5 · 8 2 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy; Ci ?, 4-91; S, 4-44; F, 7.90. Found: C, 6 1.67; Η, 5.55; Ν, 5 · &2; C ^, 4.66; S, 4.31; F, 7 · 9 5 ο Example ΐ 7 7 This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) one 232-486469 Α7 Β7 five 2. Description of the invention (230) [1 1 [[2 — [9 1 [[(2,2,2-trifluoroethyl) amino) carbonyl)] 9 9 — — 9 9 —yl] ethyl] amino] Carbonyl] Lifetime, Ernidinyl 1 amine, Formic acid, 1,1 Dimethyl ethyl ester A ·

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 2·5莫耳濃度之己烷液，110毫莫耳）於15分鐘期 間加至9 一芴羧酸（10 · 5克，50毫莫耳）之四氫呋 喃（5 0 0毫升）溶液中。再將此暗黃色溶液於〇°c下攪 拌3 0分鐘，而後將氯乙睛（3 · 8毫升，60毫莫耳） 於3分鐘期間逐滴加入。繼而將暗橘色反應混合物於〇。(： 下攪拌1 0分鐘，加溫至室溫，並攪拌3小時。再將反應 混合物以水（2 5 0毫升）及乙醚（2 5 0毫升）稀釋， 並於真空中濃縮成3 0 0毫升。而後使用1當量濃度氫氯 酸將混合物酸化成pHl · 85，再以二氯甲烷（6x 2 5 0毫升）萃取，繼而將結合之有機萃取液於硫酸鎂上 乾燥’再予過濾，及於真空中濃縮，即得固狀標題化合物 (10·45 克，76·7%)。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 233 - 486469 A7 B7 五、發明説明（231 ) B.(Please read the precautions on the back before filling out this page.) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a 2.5-mole hexane solution, 110 millimoles. Add to 9 芴 carboxylic acid in 15 minutes. (10.5 g, 50 mmol) in tetrahydrofuran (500 ml). This dark yellow solution was stirred at 0 ° C for 30 minutes, and then acetonitrile (3.8 ml, 60 mmol) was added dropwise over a period of 3 minutes. The dark orange reaction mixture was then quenched. (: Stir for 10 minutes, warm to room temperature, and stir for 3 hours. Dilute the reaction mixture with water (250 mL) and ether (250 mL) and concentrate in vacuo to 300. The mixture was acidified with 1 equivalent strength hydrochloric acid to pH 1.585, and then extracted with dichloromethane (6 x 250 ml), and the combined organic extract was dried over magnesium sulfate, and then filtered, and Concentrated in vacuum to obtain the title compound (10.45 g, 76.7%) as a solid. The paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 233-486469 A7 B7 V. Description of the invention ( 231) B.

經濟部中央標準局員工消費合作社印製 之二氯甲烷，40 · 6毫莫耳）加至第A部化合物（ 6 · 7克，2 6 · 9毫莫耳，已藉以四氫呋喃/甲苯濃縮 而乾燥）之二氯甲烷（8 0毫升）溶液中。再將反應於室 溫下攪拌1·5小時，而後於真空中濃縮，繼而於高度真 空下乾燥以得粗製醯基氯。於〇°C下，於氮下，將三乙胺 (1 1 · 3毫升，81 · 〇毫莫耳）加至2，2，2 -三 氟乙胺氫氯酸鹽（4 · 38克，32 · 4毫莫耳）之二氯 甲烷（5 0毫升）懸浮液中。繼而將所得稠厚漿液於〇。(： 下攪拌5分鐘，而後將粗製醯基氯之二氯甲烷（3 0毫升 )溶液於5分鐘期間逐滴加入。將反應混合物於〇°c下攪 拌1 0分鐘。再將二氯甲烷（1 0 0毫升）加入，而後將 溶液以1當量濃度氫氯酸（2 X 8 0毫升）及飽和碳酸氫 鈉（8 0毫升）清洗，於硫酸鈉上乾燥，過濾及於真空中 濃縮以得泡沬固狀物8 · 3克。將此物質與另一批粗製固 狀物（4 · 4克）結合。再將結合之混合物藉於矽膠（ 1 2 0 0毫升）上進行急驟色層分離，並以二氯甲烷洗提 而予以純化，即得固狀之標題化合物（10 · 5克’ 8 3 · 3 % )。 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 234 - 486469 A7 B7 五、發明説明（232 ) C·Dichloromethane printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, 40.6 millimoles, was added to the compound in Part A (6.7 grams, 26.9 millimoles, which had been concentrated and dried by tetrahydrofuran / toluene ) In dichloromethane (80 ml). The reaction was stirred at room temperature for 1.5 hours, then concentrated in vacuo, and then dried under high vacuum to obtain crude fluorenyl chloride. Triethylamine (1 1.3 ml, 81.0 mmol) was added to 2,2,2-trifluoroethylamine hydrochloride (4.38 g, 32 · 4 mmol) in dichloromethane (50 ml). The resulting thick slurry was then reduced to zero. (: Stirred for 5 minutes, and then a solution of the crude fluorenyl chloride in dichloromethane (30 ml) was added dropwise over a period of 5 minutes. The reaction mixture was stirred at 0 ° C for 10 minutes. 100 ml) was added, and then the solution was washed with 1 equivalent of hydrochloric acid (2 x 80 ml) and saturated sodium bicarbonate (80 ml), dried over sodium sulfate, filtered and concentrated in vacuo to obtain 8.3 g of foam solids. This material was combined with another batch of crude solids (4.4 g). The combined mixture was then subjected to rapid color separation on silica gel (1200 ml). And purified by diluting with dichloromethane to obtain the title compound in solid form (10 · 5g '8 3 · 3%). (Please read the precautions on the back before filling this page) This paper is for China National Standard (CNS) A4 Specification (210X297mm) _ 234-486469 A7 B7 V. Description of Invention (232) C ·

將第B部化合物（4 · 5克，1 3 · 6毫莫耳）之無 水乙醇（400毫升）/氯仿（7毫升）溶液於50 P s i下，於1 0 %鈀/碳（2 ·克）上氫化3天。再藉 通過尼龍6 6濾器中過濾以移去催化劑，而後將濾液於真 空中濃縮，即得粗製固狀之標題化合物（4·8克）。D.A solution of the compound in Part B (4.5 g, 13.6 mmol) in absolute ethanol (400 ml) / chloroform (7 ml) at 50 P si at 10% palladium / carbon (2 · g ) On hydrogenation for 3 days. The catalyst was removed by filtration through a nylon 66 filter, and the filtrate was concentrated in the air to obtain the title compound (4.8 g) as a crude solid. D.

N〇2 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於室溫下，將氯甲酸一 4 一硝苯酯（1 · 46克， 7 · 2 2毫莫耳）之四氫呋喃（2 5毫升）溶液加至粗製 第C部化合物（4 · 0克）之四氫呋喃（80毫升）及吡 啶（3 · 5毫升，43 · 4毫莫耳）溶液中。再將混合物 於室溫下攪拌過夜，於真空中濃縮以移去四氫呋喃，繼而 以乙酸乙酯（700毫升）稀釋。將乙酸乙酯以5%碳酸 氫鈉（4x50毫升），水（4x50毫升），0·2當 量濃度氫氯酸（5x50毫升），7]c (2x40毫升）及 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 235 - 486469 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（233 ) 鹽水（4 0毫升）清洗，而後於硫酸鈉上乾燥。蒸發後可 得3 · 1克泡沬狀物，將其藉於矽膠（5 00毫升）上進 行急驟色層分離，並以乙酸乙酯/己烷（20 : 80至 3 5 : 7 5 )洗提而予以純化，即得淡黃色固狀之標題化 合物（1· 59 克，41· 6%)，熔點 138 — 140 °C。 E · 〔1 一〔 〔 〔2 —〔9 一〔 〔 （2 ’ 2 ’ 2 — 三氟乙 基）胺基）羰基〕一 9H —芴一 9 一基〕乙基〕胺基〕羰 基]一4一哌啶某]胺基甲酸，1 ，1一二甲某乙酯 於氮下，將實例10第B部酯（1 · 27克， 6 · 36毫莫耳）之二氯甲烷（20毫升）溶液，繼而將 4 一二甲胺基吡啶（56毫克，0 · 46毫莫耳）加至第 D部化合物（1 · 59克，3 · 18毫莫耳）之二氯甲烷 (3 0毫升）溶液中。於室溫下攪拌過夜後，將反應混合 物以二氯甲烷（50毫升）稀釋，以0 · 1當量濃度氫氧 化鈉（3x40毫升），水（2x40毫升），1%硫酸 氫鉀（2x40毫升），水（40毫升），5%碳酸氫鈉 (2x40毫升），水（40毫升）及鹽水（40毫升） 清洗，而後於硫酸鈉上乾燥。將二氯甲烷蒸發後可得 1 · 8克泡沬狀物，將其於矽膠（100毫升）上進行急 驟色層分離，並以乙酸乙酯/己烷（60 ·· 40至100 :0 )洗提而予以純化，即得白色固狀之標題化合物（ 1 · 43 克，80· 1%)，熔點 77-80 °C。 本矣氏張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）__ 236 - (請先閲讀背面之注意事項再填寫本頁) 486469 A7 B7五、發明説明（234 ) MS (ESI ，+ 離子）m/z 5 6 1 ( Μ + Η )， 1121 (2Μ + Η); (一離子）559 (Μ—Η) 分析· C29H35N4〇4F3+〇 · 15CH2C^2 + 〇 · 4CH3C〇2C2H5之計算值： (：，60·69;Η，6·3 8;Ν，9·21 ;F，9 · 3 6 實測值·· C，6 Ο · 8 3 ; Η，6 · 3 6 ; N，9 · 2 9;F，9 · 6 1 ο 賨例1 7 8 9 —〔2 -〔〔 〔4 —(苯醯胺基）一 1 一呢陡基〕鑛基 〕胺基〕乙基〕一 N —（2，2，2 —三氟乙基）一 9H 一窃一9 一甲酿胺_；__ (請先閱讀背面之注意事項苒填寫本頁) 經濟部中央標準局員工消費合作社印製N〇2 (Please read the notes on the back before filling this page) The Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs printed the 4-chloronitroformate (1 · 46g, 7 · 2 2) at room temperature. Tetrahydrofuran (25 ml) solution was added to a solution of crude Part C compound (4.0 g) in tetrahydrofuran (80 ml) and pyridine (3.5 ml, 43.4 mmol). The mixture was stirred at room temperature overnight, concentrated in vacuo to remove tetrahydrofuran, and then diluted with ethyl acetate (700 mL). Ethyl acetate with 5% sodium bicarbonate (4x50 ml), water (4x50 ml), 0.2 equivalent hydrochloric acid (5x50 ml), 7] c (2x40 ml) and this paper size are applicable to Chinese national standards ( CNS) A4 specification (210X297 mm) 235-486469 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (233) Rinse with brine (40 ml) and then dry over sodium sulfate. After evaporation, 3.1 g of bubbly material was obtained, which was separated by flash chromatography on silica gel (500 ml) and washed with ethyl acetate / hexane (20:80 to 3 5: 7 5). After purification, the title compound (1.59 g, 41.6%) was obtained as a pale yellow solid, m.p. 138-140 ° C. E · [1 1 [[[2 — [9 1 [[((2 '2' 2-trifluoroethyl) amino) carbonyl) carbonyl]-9H —fluorene-9-yl] ethyl] amino] carbonyl]- 4-piperidine] Aminocarboxylic acid, 1,1,2-dimethylethyl under nitrogen, Example 10 Part B ester (1.27 g, 6.36 mmol) in dichloromethane (20 ml ) Solution, then 4-dimethylaminopyridine (56 mg, 0.46 mmol) was added to the D compound (1.59 g, 3.18 mmol) in methylene chloride (30 ml ) In solution. After stirring overnight at room temperature, the reaction mixture was diluted with dichloromethane (50 ml), 0.1% sodium hydroxide (3 x 40 ml), water (2 x 40 ml), 1% potassium hydrogen sulfate (2 x 40 ml). Wash with water (40 ml), 5% sodium bicarbonate (2 x 40 ml), water (40 ml) and brine (40 ml), then dry over sodium sulfate. Evaporation of dichloromethane gave 1.8 g of bubbly, which was separated on silica gel (100 ml) in a flash layer, and washed with ethyl acetate / hexane (60 ·· 40 to 100: 0). Elution and purification gave the title compound (1.43 g, 80.1%) as a white solid with a melting point of 77-80 ° C. This Chang's scale is applicable to the Chinese National Standard (CNS) A4 specification (21.0X297 mm) __ 236-(Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (234) MS (ESI, + Ion) m / z 5 6 1 (M + +), 1121 (2M + Μ); (one ion) 559 (Μ—Η) analysis · C29H35N4〇4F3 + 〇 · 15CH2C ^ 2 + 〇 · 4CH3C〇2C2H5 calculation Values: (:, 60 · 69; Η, 6.3 8; N, 9 · 21; F, 9 · 3 6 Measured value · C, 6 Ο · 8 3; Η, 6 · 3 6; N, 9 · 2 9; F, 9 · 6 1 ο Example 1 7 8 9 — [2-[[[[4 -— (Benzamidoamino)-1-N-stilbyl] mine-based] amino] ethyl] -N — (2,2,2—Trifluoroethyl) —9H—Stolen—9—Methylamine _; __ (Please read the notes on the back first and fill in this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy

將4當量濃度氫氯酸之二噁烷液（9毫升，36 · 4 毫莫耳）加至實例177化合物（1 _ 1克，1 · 97毫 莫耳）之四氫呋喃（4毫升）溶液中。再將反應混合物於 室溫下攪拌3小時，而後於真空中濃縮’繼而由二噁烷（ 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐） 486469 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（235 ) 3 X 1 0毫升）中濃縮，即得泡沬固狀之標題化合物（ 1 · 4 6 克）。 B· 9 -〔2 —〔〔〔4 一（苯醯胺基）一 1一哌啶基 〕羰基〕胺基〕乙基〕一 N —（2，2，2 —三氟乙基） 一 9H -芴一9 一甲醯胺_____ 於0°C下，將苯醯氯（172微升，1 · 47毫莫耳 )逐滴加至粗製第A部化合物（7 3 0毫克，0 · 9 8毫 莫耳）及三乙胺（6 1 5微升，4 · 4 1毫莫耳）之二氯 甲烷（1 0毫升）溶液中。再將反應於0°C下攪拌3 0分 鐘，而後以二氯甲烷（3 0毫升）稀釋。繼而將溶液以 0 · 1當量濃度氫氧化鈉（2x40毫升），水（40毫 升），0·2當量濃度氫氯酸（2x40毫升），水（ 4 0毫升）及鹽水（4 0毫升）清洗，而後於硫酸鎂上乾 燥，並濃縮成白色固狀物（1 · 6克）。將此固狀物於矽 膠（1 0 0毫升）上藉5%甲醇之二氯甲烷液洗提而予以 純化，即得白色固狀之標題化合物（4 2 7毫克， 7 7 · 2 % )。 熔點· 220 — 222 °C MS (ESI ，+ 離子）m/z 5 6 5 ( Μ + Η )， 5 8 2 ( Μ + Ν Η 4 )； (―離子）5 63 (Μ - Η)。 分析· c31h31n4o3f3之計算值： C，6 5.95;H，5.53;N，9-92 本紙張尺度適用中國國家標準（CNS ) A4規格（21,0X297公釐）—238 - (請先閱讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（236 ) ;F，1 0 · 0 9 實測值：C，65-80 ;Η，5·41;Ν，9·84 ;F，9 · 9 8 ° 實例1 7 Q 4 一〔〔 （1 ，1 一二甲基乙氧基）羰基〕胺基〕—1 一 哌啶羧酸，2 —〔9-〔〔 （2，2，2 —三氟乙基）胺 基〕羰某Ί 一 9 Η -芴一 9 —某1乙醋 _A solution of 4 equivalents of hydrochloric acid in dioxane (9 ml, 36.4 mmol) was added to a solution of the compound of Example 177 (1-1 g, 1.97 mmol) in tetrahydrofuran (4 ml). The reaction mixture was stirred at room temperature for 3 hours, and then concentrated in a vacuum, and then consumed by dioxane (this paper size applies Chinese National Standard (CNS) A4 specification (21.0X297 mm) 486469 staff of the Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed A7 B7 V. Description of the invention (235) 3 X 10 ml) was concentrated to obtain the title compound (1.46 g) in the form of foam. B · 9-[2 — [[[4-((Phenylamino)-1-piperidinyl] carbonyl] amino] ethyl] ethyl] -N— (2,2,2-trifluoroethyl) —9H -芴 -9 Monomethylamine _____ Add phenylhydrazone chloride (172 μl, 1. 47 mmol) to the crude Part A compound (7 3 0 mg, 0 · 9 at 0 ° C) 8 millimoles) and triethylamine (6 15 microliters, 4.41 millimoles) in dichloromethane (10 ml). The reaction was stirred at 0 ° C for 30 minutes and then diluted with dichloromethane (30 ml). The solution was then washed with 0.1 equivalent sodium hydroxide (2x40 ml), water (40 ml), 0.2 equivalent hydrochloric acid (2x40 ml), water (40 ml) and brine (40 ml). Then it was dried over magnesium sulfate and concentrated to a white solid (1.6 g). This solid was purified on a silica gel (100 ml) by eluting with 5% methanol in dichloromethane to obtain the title compound (427 mg, 77 · 2%) as a white solid. Melting point 220 — 222 ° C MS (ESI, + ion) m / z 5 6 5 (M + Η), 5 8 2 (M + Ν Η 4); (―ion) 5 63 (M-Η). Analysis · Calculated values of c31h31n4o3f3: C, 6 5.95; H, 5.53; N, 9-92 This paper size is applicable to China National Standard (CNS) A4 specification (21,0X297 mm)-238-(Please read the note on the back first Please fill in this page again for matters) 486469 A7 B7 V. Description of the invention (236); F, 10 · 0 9 Measured value: C, 65-80; Η, 5. · 41; N, 9. 84; F, 9 · 9 8 ° Example 1 7 Q 4 mono-[[(1,1-dimethylethoxy) carbonyl] amino] -1 monopiperidinecarboxylic acid, 2- [9-[[(2,2,2 —tri Fluoroethyl) amino] carbonyl a Ί a 9 Η-芴 a 9 — a 1 ethyl acetate _

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於0°C下，於氬下，將35 · 2毫升2 · 5莫耳濃度 正丁基鋰之己烷液（8 8毫莫耳）於1 5分鐘期間加至已 攪拌之8 · 4 1克（40毫莫耳）9 一芴羧酸之400毫 升無水四氫呋喃溶液中。再將反應於0°C下攪拌3 0分鐘 ，而後將4 · 2毫升（48 · 5毫莫耳）烯丙基溴於15 分鐘期間加入。再將反應於0°C下攪拌1 5分鐘，及於室 溫下攪拌1小時，繼而加入水（8 0毫升）以令反應中止 。再將四氫呋喃於真空中移除，將水性混合物以乙醚（ 2 X 1 0 0毫升）萃取。繼而將水性層以二氯甲烷（ 1 5 0毫升）層化，而後以1當量濃度氫氯酸酸化（pH < 2 )。萃取後，將水性相以另外之二氯甲烷（ 2 X 1 0 0毫升）萃取，再將結合之二氯甲烷萃取液以水 本纸張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐）_ ug - 486469 A7 B7 五、發明説明（237 ) 清洗，乾燥（硫酸鎂）及濃縮，即得9 · 41克（94% )無定形固狀之標題化合物。 B·(Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed it at 0 ° C under argon and applied 35 · 2 ml of 2.5 · 5 Molar concentration of n-butyl lithium. The alkane solution (88 mmol) was added to a stirred solution of 8.4.1 g (40 mmol) of 9 monocarboxylic acid in 400 ml of anhydrous tetrahydrofuran over a period of 15 minutes. The reaction was stirred at 0 ° C for 30 minutes, and then 4.2 ml (48.5 mmol) allyl bromide was added over 15 minutes. The reaction was stirred at 0 ° C for 15 minutes and at room temperature for 1 hour, and then water (80 ml) was added to stop the reaction. Tetrahydrofuran was removed in vacuo, and the aqueous mixture was extracted with diethyl ether (2 × 100 ml). The aqueous layer was then layered with dichloromethane (150 ml) and then acidified with 1 equivalent of hydrochloric acid (pH < 2). After the extraction, the aqueous phase was extracted with another dichloromethane (2 × 100 ml), and the combined dichloromethane extract was applied to the paper standard of water based on Chinese National Standard (CNS) A4 (2 丨 0X297 (Mm) _ ug-486469 A7 B7 5. Description of the invention (237) Wash, dry (magnesium sulfate) and concentrate to obtain 9.41 g (94%) of the title compound as an amorphous solid. B ·

經濟部中央標隼局員工消費合作社印製 將第A部化合物（9 · 3 0克）藉於真空中由無水四 氫呋喃及無水甲苯之混合液中濃縮（2次予以乾燥。於 氮下，將2 8毫升2 · 0莫耳濃度草醯氯之二氯甲烷（ 5 5 · 8毫莫耳）液小心加至已攪拌之此酸之1 0 〇毫升 無水二氯甲烷及1 4 3毫升二甲基甲醯胺溶液中。再將反 應於室溫下攪拌1 · 5小時，而後於真空中濃縮，繼而於 0 · 5毫米下乾燥1小時以得第A部酸之粗製醯基氯。於 〇°C下，於氬下，將三乙胺（15 · 6毫升，11 2毫莫 耳）加至已攪拌之6 · 04克（44 · 6毫莫耳）2，2 ，2 —三氟乙胺氫氯酸鹽之7 5毫升無水二氯甲烷懸浮液 中。再將漿液於0°C下攪拌1 〇分鐘，而後邊保持內溫 < 1 2°C，邊將粗製醯基氯之3 5毫升二氯甲烷溶液於 1 0分鐘期間加入。再將反應於0°C下攪拌1 5分鐘及於 室溫下攪拌1小時，而後以1 5 0毫升二氯甲烷稀釋。將 二氯甲烷以1當量濃度氫氯酸（2x75毫升），水（ 180毫升），5%碳酸氫鈉（120毫升），及水（ 2 X 1 80毫升）清洗，並予乾燥（硫酸鈉）及濃縮成餘 留物（12· 67克）。將此餘留物於500克矽膠上進 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X29?公釐） -240 - 486469 A7 B7 五、發明説明（238 ) 行色層分離，即得10 · 74克（87%)無定形白色固 狀之標題化合物，熔點· 84 — 86 °C。 C. !Printed by the Employees' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs. The compound of Part A (9.30 g) was concentrated in a vacuum from a mixture of anhydrous tetrahydrofuran and anhydrous toluene (dried twice. Under nitrogen, 2 8 ml of 2.0 ml molar dichloromethane (55. 8 mmol) dichloromethane solution was carefully added to the stirred 100 ml of anhydrous dichloromethane and 143 ml of dimethyl In the formamide solution, the reaction was stirred at room temperature for 1.5 hours, then concentrated in vacuo, and then dried at 0.5 mm for 1 hour to obtain the crude fluorenyl chloride of Part A acid. At 0 ° Under C, add triethylamine (15. 6 ml, 112 mmol) to 6.4 g (44. 6 mmol) of 2, 2, 2, trifluoroethylamine under argon. 7.5 ml of hydrochloride in a suspension of anhydrous dichloromethane. The slurry was stirred at 0 ° C for 10 minutes, while maintaining the internal temperature < 12 ° C, while the crude fluorenyl chloride was 3 5 Methylene chloride solution was added over 10 minutes. The reaction was stirred at 0 ° C for 15 minutes and at room temperature for 1 hour, and then 150 mL of dichloromethane was added. Diluted. Dichloromethane was washed with 1 equivalent of hydrochloric acid (2 x 75 mL), water (180 mL), 5% sodium bicarbonate (120 mL), and water (2 X 180 mL), and dried (sulfuric acid Sodium) and concentrated into a residue (12. 67 grams). This residue is put on 500 grams of silicone (please read the precautions on the back before filling this page) The paper size applies to Chinese National Standard (CNS) A4 Specifications (21.0X29? Mm) -240-486469 A7 B7 V. Description of the invention (238) The color layer is separated to obtain 10.74 g (87%) of the title compound as an amorphous white solid, melting point 84-86 ° C. C.!

經濟部中央標隼局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 於一 55 °C下，令臭氧（於氧中）通過已攪拌之 5 · 30克第B部化合物之8 0毫升無水甲醇溶液中1小 時，於一 5 5 °C下，令氮起泡通過反應中1 0分鐘，而後 將反應加溫至一 3 0°C，而後將已冷卻至0°C之氫硼化鈉 (9 08毫克，24毫莫耳）之20毫升50%水性甲醇 溶液加入，再將反應於一 3 0°C下攪拌7 0分鐘。繼而移 去冷卻浴，將pH調整至<pH2 (3當量濃度氫氯酸） ’再將反應濃縮以移去甲醇。令餘留物分界於乙酸乙酯及 水間，再將乙酸乙酯以水清洗（4次），乾燥（硫酸鈉） 及濃縮以得餘留物（6 · 67克）。而後將餘留物於 4 7 5克矽膠上進行色層分離並先以己烷-乙酸乙酯（6 :4 )，後以己烷一乙酸乙酯（1 : 1 )洗提，即得 2 · 77克（49%)無定形固狀之標題化合物。較早洗 提之溶離份可得1 · 9 7克化合物Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (please read the precautions on the back before filling out this page). At a temperature of 55 ° C, allow ozone (in oxygen) to pass through 5 · 30 grams of the Part B compound that has been stirred. In 80 ml of anhydrous methanol solution for 1 hour, at -55 ° C, nitrogen was bubbled through the reaction for 10 minutes, and then the reaction was heated to 30 ° C, and then cooled to 0 ° C. 20 ml of 50% aqueous methanol solution of sodium borohydride (9 08 mg, 24 mmol) was added, and the reaction was stirred at 30 ° C. for 70 minutes. The cooling bath was then removed, and the pH was adjusted to < pH 2 (3 equivalents of hydrochloric acid) 'and the reaction was concentrated to remove methanol. The residue was delimited between ethyl acetate and water. The ethyl acetate was washed with water (4 times), dried (sodium sulfate), and concentrated to obtain the residue (6.67 g). Then the residue was separated on 475 g of silica gel and separated with hexane-ethyl acetate (6: 4) and then hexane-ethyl acetate (1: 1) to obtain 2 77 g (49%) of the title compound as an amorphous solid. 1.7 g of compound were obtained from the earlier eluted fractions

本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）_ 241 486469 A7 __B7 五、發明説明（239 )This paper size applies to Chinese National Standard (CNS) A4 specification (21.0X297 mm) _ 241 486469 A7 __B7 V. Description of the invention (239)

N〇2 經濟部中央標準局員工消費合作社印製 於室溫下，於氬下，將氯甲酸4一硝苯酯（1·2克 ，6毫莫耳）加至已攪拌之1 · 34克（4毫莫耳）第C 部化合物及0 · 97毫升（12毫莫耳）無水吡啶之1 5 毫升二氯甲烷溶液中。再將反應於室溫下攪拌2 0分鐘， 而後以二氯甲烷稀釋。繼而將二氯甲院溶液以5 %碳酸氫 鈉（4次），水，稀氫氯酸（2次），及水（3次）清洗 ，再予乾燥（硫酸鈉）及濃縮，即得泡沬餘留物形式之粗 製標題化合物（2· 30克）。 E · 4 —〔〔 （1 ，1—二甲基乙氧基）羰基〕胺基〕 一 1 一哌啶羧酸，2 —〔9一〔 〔 （2 ，2 ，2 —三氟乙 基）胺某]羰基]一9H—芴一9一某1乙酷_ 於室溫下，於氬下，將4 一 B 〇 c -胺基哌啶（ 1 · 58克，7 · 90毫莫耳）加至已攪拌之2 · 29克 上示第D部化合物之3 0毫升無水二氯甲烷溶液中。再將 反應於室溫下攪拌2小時，而後以二氯甲烷稀釋。繼而將 二氯甲烷溶液以稀氫氧化鈉（2次），水（2次），稀硫 酸氫鉀（2次）及水（3次）清洗，並予乾燥（硫酸鈉） 及濃縮以得2 · 6 3克油狀餘留物。將此餘留物於2 3 0 本紙張尺度適用中國國家標準（CNS ) A4規格1210X297公釐）_ 242 - ' ' (請先閲讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（240 ) 克矽膠上使用己烷-乙酸乙酯（6 : 4)進行色層分離，No.2 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs at room temperature, under argon, add 4-nitrophenyl chloroformate (1.2 g, 6 mmol) to the stirred 1.34 g (4 mmol) of compound C and 15 ml of dichloromethane solution of 0.997 ml (12 mmol) of anhydrous pyridine. The reaction was stirred at room temperature for 20 minutes and then diluted with dichloromethane. Then, the dichloromethane solution was washed with 5% sodium bicarbonate (4 times), water, dilute hydrochloric acid (2 times), and water (3 times), and then dried (sodium sulfate) and concentrated to obtain foam粗 The crude title compound as a residue (2.30 g). E · 4 -— [[(1,1-Dimethylethoxy) carbonyl] amino] -1 1-piperidinecarboxylic acid, 2- [9-[[(2,2,2-trifluoroethyl) Amine] carbonyl] -9H—9-9-1 1 ethyl _ 4-B occ-aminopiperidine (1.58 g, 7.90 millimolar) at room temperature under argon Add to a stirred solution of 2.29 g of the compound of Part D shown in 30 ml of anhydrous dichloromethane. The reaction was stirred at room temperature for 2 hours and then diluted with dichloromethane. Then the dichloromethane solution was washed with dilute sodium hydroxide (2 times), water (2 times), dilute potassium hydrogen sulfate (2 times) and water (3 times), and dried (sodium sulfate) and concentrated to obtain 2 · 63 grams of oily residue. Apply this residue to 2 3 0 This paper size applies Chinese National Standard (CNS) A4 size 1210X297 mm) 242-'' (Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (240) g of silica gel was subjected to chromatographic separation using hexane-ethyl acetate (6: 4),

繼而由乙酸乙酯-己烷中予以結晶，即得2 · 0 7克（ 94%)白色固狀之標題化合物。熔點120 — 12 2 °C 〇 分析· C29H34F3N3〇5+0 · 5CH3C〇2C2H5 之 計算值：（：，61·48;Η，6·3 2;Ν，6·94 ;F，9 · 4 1 實測值：C，6 1 · 2 5 ; Η，6 · 3 9 乂 Ν，6 · 8 5 ;F，9 · 4 2 〇 MS (ESI - ΝΗ3，+ 離子）562 (Μ + Η)， 5 7 9 ( Μ + Ν Η 4 )； (一離子）5 6 0。 實例1 8 Ο 4 一〔 （2 -苯氧基苯醯）胺基〕一 1 一哌啶羧酸，2 -〔9 一〔〔 （2，2，2 —三氟乙基）胺基〕羰基〕一 9 Η -荀一 9 一基〕乙醋__ 經濟部中央標準局員工消費合作社印製 Α.Crystallization from ethyl acetate-hexane gave 2.07 g (94%) of the title compound as a white solid. Melting point 120 — 12 2 ° C 〇 Analysis · Calculated for C29H34F3N3 05 + 0 5CH3C〇2C2H5: (:, 61 · 48; Η, 6. · 2 2; Ν, 6.94; F, 9 · 4 1 Measured Values: C, 6 1 · 2 5; Η, 6 · 3 9 乂 Ν, 6 · 8 5; F, 9 · 4 2 〇MS (ESI-ΝΗ3, + ion) 562 (Μ + Η), 5 7 9 (Μ + Ν Η 4); (monoion) 5 6 0. Example 1 8 Ο 4-[(2-phenoxyphenylhydrazine) amino]-1 -piperidinecarboxylic acid, 2-[9-[[ (2,2,2-trifluoroethyl) amino group] carbonyl group] 9 Η-荀 9 9 1 group] ethyl acetate __ Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α.

(請先閱讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

NH2 · HCI 於氬下，於室溫下，將6毫升4當量濃度氫氯酸之二 噁烷液（24毫莫耳）加至898毫克（1 · 6毫莫耳） 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 243 - 486469 A7 B7 五、發明説明（24i) 實例1 7 9化合物之3毫升無水四氫呋喃溶液中。再將反 應於室溫下攪拌2小時，而後於5 °C下貯存過夜。繼而將 反應於真空中濃縮，再由無水二噁烷（2 X 5毫升）中濃 縮，再於0 · 5毫米下乾燥2小時，即得無定形餘留物形 式之粗製標題化合物。 B.NH2 · HCI Under argon at room temperature, add 6 ml of 4 equivalents of hydrochloric acid dioxane solution (24 millimoles) to 898 mg (1.6 millimoles) Standard (CNS) A4 specifications (210X297 mm) _ 243-486469 A7 B7 V. Description of the invention (24i) Example 1 3 Compound in 3 ml of anhydrous tetrahydrofuran solution. The reaction was stirred for another 2 hours at room temperature and then stored at 5 ° C overnight. The reaction was then concentrated in vacuo, concentrated in anhydrous dioxane (2 x 5 ml), and dried at 0.5 mm for 2 hours to obtain the crude title compound as an amorphous residue. B.

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作杜印製(Please read the notes on the back before filling out this page) Printed by the Department of Economics, Central Bureau of Standards, Consumer Cooperation

於0°C下，於氮下，將1 · 5毫升2 · 0莫耳濃度草 醯氯之二氯甲烷液（3 · 0毫莫耳）加至4 2 8毫克（ 2·0毫莫耳）2—苯氧基苯甲酸及10微升二甲基甲醯 胺之4毫升無水二氯甲烷液中。再將反應於室溫下攪拌 1 · 5小時，而後於真空中濃縮，繼而於0 · 5毫米下乾 燥1小時以得淡黃色油狀之粗製標題醯基氯。令此油狀物 溶於3·2毫升二氯甲烷中。 C · 4 —〔 （2 -苯氧基苯醯）胺基〕—1—哌啶羧酸 ，2 —〔9 一〔〔 （2，2，2 —三氟乙基）胺基〕羰基 1 一 9H —芴一 9 一某1乙醋_ 於0°C下，於氬下，將0 · 46毫升（4毫莫耳）三 乙胺加至已攪拌之上示一半之第A部化合物粗製製劑（約 0·8毫莫耳）之4毫升無水二氯甲烷溶液中。再將溶液 於0°C下攪拌5分鐘，而後將2 · 0毫升整份之上示第B 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）.244- 486469 A7 B7 經濟部中央標準局員工消費合作社印製 五、發明説明（242 ) 部化合物之3 · 2毫升二氯甲烷溶液（約1 · 2毫莫耳之 粗製第B部化合物）加入。再將反應於〇°c下攪拌2 · 5 小時，而後以二氯甲烷稀釋，繼而將二氯甲烷以稀氫氧化 鈉（2次）’水（2次），稀氫氯酸（2次）及水（3次 )清洗’並予乾燥（硫酸鈉）及濃縮成稠厚油狀物（ 577毫克）。再將此油狀物於45克矽膠上使用己烷一 乙酸乙酯（1 :1)進行色層分離，即得414毫克熔點 爲6 8 — 7 3 °C之泡沬狀標題化合物（7 9 % )。 分析· C37H34NF3N3〇5+〇 · 2CH3C02C2H5 之 5十算值.C ’ 6 7 · 2 3 ; Η，5 · 3 1 ; N，6*22;F，8.44 實測值·· C，6 7 · 〇 4 ; Η，5 · 2 Ο ; N，6 · 1 8 ;F，8 · 7 Ο。 MS (ESI — ΝΗ3，+ 離子）658 (Μ + Η)， 675 (Μ+ΝΗ4)。 實例1 8 1 9 一〔4 一〔4 一〔 （2 -苯氧基苯醯）胺基〕一 1—哌 啶基〕戊基〕一 N -（2，2，2 -三氟乙基）一 9H — 葱一 9 一甲醯胺，單氣氳酸鹽 _ 將實例175化合物（1 · 25克，2 · 23毫莫耳 )之1 0毫升4當量濃度氫氯酸之二噁烷溶液攪拌（以氯 化鈣乾燥管保護）3小時。再將溶液於3 0 °C下蒸發，而 後令所得固狀物再以二氯甲烷溶解成2 0 · 0毫升之總量 -----------------1T------Φ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469At 0 ° C under nitrogen, add 1.5 ml of a 2.0 ml molar solution of chloramphenicol in dichloromethane (3.0 mmol) to 4 2 mg (2.0 mmol) ) 2-phenoxybenzoic acid and 10 μl of dimethylformamide in 4 ml of anhydrous dichloromethane. The reaction was further stirred at room temperature for 1.5 hours, then concentrated in vacuo, and then dried at 0.5 mm for 1 hour to give the crude title fluorenyl chloride as a pale yellow oil. This oil was dissolved in 3.2 ml of dichloromethane. C · 4 -— ((2-phenoxyphenylhydrazone) amino] -1-piperidinecarboxylic acid, 2- [9-[[(2,2,2-trifluoroethyl) amino] carbonyl 1- 9H — 9-9 1 ethyl acetate_ At 0 ° C, under argon, add 0.46 ml (4 millimolar) of triethylamine to the half of the crude part A compound preparation. (About 0.8 millimoles) in 4 ml of anhydrous dichloromethane. The solution was stirred at 0 ° C for 5 minutes, and then the entire 2.0 ml portion is shown on the top. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (21.0X297 mm). 244-486469 A7 B7 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China. 5. Description of the Invention (242) 3.2 ml of dichloromethane solution of the compound (about 1.2 mmol of the crude Part B compound) was added. The reaction was stirred at 0 ° C for 2.5 hours, then diluted with dichloromethane, and then the dichloromethane was diluted with dilute sodium hydroxide (twice) 'water (twice) and dilute hydrochloric acid (twice) Wash with water (3 times), and dry (sodium sulfate) and concentrate to a thick oil (577 mg). This oil was separated on 45 g of silica gel using hexane-ethyl acetate (1: 1) to obtain 414 mg of the title compound (7 9 %). Analysis · C37H34NF3N3〇5 + 〇 2CH3C02C2H5 50 counts. C '6 7 · 2 3; Η, 5 · 3 1; N, 6 * 22; F, 8.44 found value · C, 6 7 · 〇4 Η, 5 · 2 〇; N, 6 · 1 8; F, 8 · 7 〇. MS (ESI — ΝΗ3, + ion) 658 (Μ + Η), 675 (Μ + ΝΗ4). Example 1 8 1 9 1 [4 1 [4 1 [(2-phenoxyphenylhydrazone) amine] 1-piperidinyl] pentyl] 1 N-(2,2,2-trifluoroethyl) 9H — Allium-9 monomethylammonium monomonoxide, 10 ml of a 4-equivalent solution of hydrochloric acid in dioxane, Example 175 (1.25 g, 2.23 mmol) was stirred (Protected with calcium chloride drying tube) for 3 hours. The solution was evaporated at 30 ° C, and then the obtained solid was dissolved in dichloromethane to a total of 20 · 0 ml ------ 1T ------ Φ (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 486469

經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（243 ) ，將三乙胺（0·4毫升，2·9毫莫耳），而後將2-苯氧基苯醯氯（320毫克，1 · 38毫莫耳）之10毫 升二氯甲烷溶液於1 〇分鐘期間加至已於氬下冷卻至 一 10 °C之10 · 0毫升此攪拌溶液（約1 · 12毫莫耳 )中。1小時後，使用飽和碳酸氫鈉溶液令反應中止，再 以乙酸乙酯萃取兩次。而後將有機萃取液乾燥（硫酸鈉） 及蒸發。再藉急驟色層分離法（5 X 2 0公分柱，乙酸乙 酯作爲洗提液）予以純化以得無色油狀物（6 0 3毫克， 77%)，令此油狀物溶於5毫升乙酸乙酯中，而後將 〇·25毫升4當量濃度氫氯酸之二噁烷液加入，再將乙 醚加入直至形成膠黏沈澱物爲止。於真空中潷析及乾燥後 ’即得白色固狀之標題化合物（650毫克），熔點 136 - 138 0C。 分析· C39H40F3N3〇3+HC 艾 + H2〇： C，65-95;H，6.10;C^，4.9 9;F，8-02;N，5.92 實測值：C，65-87;H，6.08; Cj?，5.13;F，7.96;N，5.92 ο MS (電噴霧，+ 離子）m/e 654 (M + H)。 實例182至187 遵循上文及工作實例中所示之步驟，即製得下列化合 物。 本紙張尺度適用中國國家標準（CNS ) A4規格（2L0X297公釐）__ 246 (請先閲讀背面之注意事項再填寫本頁) 486469A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the Invention (243) Triethylamine (0.4 ml, 2.9 mmol), and then 2-phenoxyphenylhydrazone (320 10 milligrams of dichloromethane solution (mg, 1.38 millimoles) was added over 10 minutes to 10 · 0 milliliters of this stirred solution (about 1.12 millimoles) which had been cooled to a temperature of 10 ° C under argon. in. After 1 hour, the reaction was stopped using a saturated sodium bicarbonate solution, and extracted twice with ethyl acetate. The organic extract was then dried (sodium sulfate) and evaporated. It was purified by flash chromatography (5 X 20 cm column, ethyl acetate as eluent) to obtain a colorless oil (603 mg, 77%). The oil was dissolved in 5 ml In ethyl acetate, 0.25 ml of a 4 equivalent solution of hydrochloric acid in dioxane was added, and then ether was added until a gummy precipitate formed. After decanting and drying in vacuo, the title compound (650 mg) was obtained as a white solid, melting at 136-138 0C. Analysis · C39H40F3N3 03 + HC AI + H 2 0: C, 65-95; H, 6.10; C ^, 4.99; F, 8-02; N, 5.92 Found: C, 65-87; H, 6.08; Cj ?, 5.13; F, 7.96; N, 5.92 o MS (electrospray, + ion) m / e 654 (M + H). Examples 182 to 187 Following the steps shown above and in the working examples, the following compounds were prepared. This paper size applies to Chinese National Standard (CNS) A4 specification (2L0X297 mm) __ 246 (Please read the precautions on the back before filling this page) 486469

經濟部中央標隼局員工消費合作社印製 A7 B7_五、發明説明（244 )實例1 8 2 9 一〔2 -〔〔 〔4 一〔 （2 —苯氧基苯醯）胺基〕—1 一哌啶基〕羰基〕胺基〕乙基〕—N -（ 2，2，2 -三 氟乙基）一 9 Η —荀一 9 一甲醯胺 MS (ESI ，+ 離子）：657 (M + H) 分析· C37H35N4〇4F3+0 · 2 C H 2 C ^ 2 + 0 · 1 C Η 3 C 0 2 C 2Η 5之計算值： (：，66·17;Η，5·35;Ν，8·21 ;F，8 · 3 5 實測值：（：，66·14;Η，5·29;Ν，8·13 ;F，8 · 4 7 〇 熔點 84-87ΐ。 實例1 8 3 4 一（苯醯胺基）一 1 一哌啶羧酸，2 —〔9 一〔〔 （2 ，2，2 -三氟乙基）胺基〕羰基〕一 9Η —芴一 9 一基 〕乙酯 MS (ESI - ΝΗ3，+ 離子）：566 (Μ + Η) 分析· C3iH3OF3N3〇4+0 · 2CH3C〇2C2H5 + Ο · 25H2〇之計算值： (：，64·99;Η，5·51;Ν，7·04 ;F，9 · 7 Ο 實測值：C，6 4 · 7 7 ; Η，5 · 4 5 ; N，7 · 1 5 本紙張尺度適用中國國家標準（CNS ) Α4規格（21.0X297公釐）_ 247 一 (請先閲讀背面之注意事項再填寫本頁) 486469 A7 _B7 _ 五、發明説明（245 ) ;F，1 0 · 1 0 ° 熔點 75-85 °C。 實例1 8 4 9一〔4一〔4 —(苯醯胺基）_1 一哌啶基〕戊基〕一 N — (2 ，2 ，2 —三氟乙基）一 9H —荀一 9 一甲醯胺 ，單氫氯酸鹽 M S (電噴霧，+ 離子）m / z 5 6 4 (Μ + Η ) 分析· （：331136?31^3〇2+«[(：义+112〇之計算值： C，64-12;H，6，36; Cj?，5.74;F，9-22;N，6-80 實測值：C，6 4 · 1 7 ; Η，6 · 2 7 ;Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7_V. Description of the Invention (244) Example 1 8 2 9 1 [2-[[[4 1 [(2 —phenoxyphenylhydrazone) amine group] -1] Monopiperidinyl] carbonyl] amino] ethyl] -N-(2,2,2-trifluoroethyl)-9 Η-荀-9 monomethylamine (MSI, + ion): 657 (M + H) Analysis · C37H35N4〇4F3 + 0 · 2 CH 2 C ^ 2 + 0 · 1 C Η 3 C 0 2 C 2Η 5 Calculated: (:, 66 · 17; Η, 5.35; Ν, 8 · 21; F, 8 · 3 5 Measured value: (:, 66 · 14; Η, 5.29; N, 8.13; F, · 4.7 melting point 84-87ΐ. Example 1 8 3 4-( Phenylamino)-1-piperidinecarboxylic acid, 2- [9-[[((2,2,2-trifluoroethyl) amino] carbonyl]-9-fluorene-9-yl] ethyl ester MS ( ESI-ΝΗ3, + ion): 566 (Μ + Η) Analysis · Calculated for C3iH3OF3N3〇4 + 0 · 2CH3C〇2C2H5 + 0 · 25H2〇: (:, 64 · 99; Η, 5.51; Ν, 7 · 04; F, 9 · 7 〇 Actual measured value: C, 6 4 · 7 7; Η, 5 · 4 5; N, 7 · 1 5 This paper size applies to China National Standard (CNS) Α4 specification (21.0X29 7mm) _ 247 I (Please read the notes on the back before filling this page) 486469 A7 _B7 _ V. Description of the invention (245); F, 1 0 · 1 0 ° Melting point 75-85 ° C. Example 1 8 4 9- [4- [4- (phenylamidinyl) _1-piperidinyl] pentyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-methylformamide, Monohydrochloride MS (electrospray, + ion) m / z 5 6 4 (Μ + Η) Analysis · (: 331136? 31 ^ 3〇2 + «[(: Yi + 112〇 calculated value: C, 64-12; H, 6, 36; Cj ?, 5.74; F, 9-22; N, 6-80 Found: C, 6 4 · 1 7; Η, 6 · 2 7;

Cj?，5.65;F，9.65;N，6.60 ο 熔點 1 3 0 - 1 3 2 °C。 實例1 8 5 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 9 -〔4 —〔4 一〔〔 （1 ，1—二甲基乙氧基）羰基〕 胺基〕一 1 一哌啶基〕丁基〕—N— (2，2，2-三氟 乙基）一9 Η — _噸一9 一甲醯胺 熔點 7 6 - 7 9 °C。 MS (ES ，+ 離子，NH3) m/z 5 7 8 ( Μ + Η ^ 〇 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ 248 - 486469 A7 B7五、發明説明（246 ) 實例1 8 6 9 —〔4-〔4 一（苯醯胺基）一 1 一哌啶基〕丁基〕一 N —（2 ，2 ，2_三氟乙基）一9H —瞎噸一 9 一甲醯 胺 熔點 1 6 7 — 1 6 9 °C。 MS (ES，+ 離子，NH3)m/z 5 8 2 ( M + ΗCj ?, 5.65; F, 9.65; N, 6.60 ο Melting point 1 3 0-1 3 2 ° C. Example 1 8 5 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 9-[4 — [4 1 [[(1,1-dimethylethoxy) carbonyl ] Amine]-1-piperidinyl] butyl] -N-(2,2,2-trifluoroethyl)-9 Η-_ ton-9 monomethylamine melting point 7 6-7 9 ° C. MS (ES, + ion, NH3) m / z 5 7 8 (Μ + Η ^ 〇 This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 248-486469 A7 B7 V. Description of the invention (246 ) Example 1 8 6 9 — [4- [4 (Phenylamino)-1-piperidinyl] butyl] -N — (2, 2, 2, 3-trifluoroethyl) — 9H — blind ton 9 Monomethylamine melting point 1 6 7 — 1 6 9 ° C. MS (ES, + ion, NH3) m / z 5 8 2 (M + Η

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

實例1 8 7 9 一〔4 一〔4 一〔〔 （2 —苯氧基苯基）羰基〕胺基〕 一 1 一哌啶基〕丁基〕—N -（2，2，2 -三氟乙基） 一9H—晦噸一9一甲醯胺 熔點 1 6 4 - 1 6 6 °C。 MS (ES，+ 離子，NH3)m/z 674 (M + H 根據本發明，其乃提供作爲Μ T P抑制劑之另一類理 想化合物，彼具有下列之結構 X1Example 1 8 7 9 1 [4 1 [4 1 [[(2-phenoxyphenyl) carbonyl] amino] 1 1 piperidinyl] butyl] -N-(2,2,2-trifluoro (Ethyl) 9H-Heptazone-9-Methylformamide Melting point 1 6 4-16 6 ° C. MS (ES, + ion, NH3) m / z 674 (M + H According to the present invention, it provides another ideal class of compounds as MT inhibitors, which have the following structure X1

Ο 其中Ζ爲一個鍵，0或S ; 本紙張尺度適用中國國家標準（CNS ) Α4規格（21.0X297公釐）_ 249 (請先閎讀背面之注意事項再填寫本頁) .41^衣· 486469 經濟部中央標準局員工消費合作社印製 ， A7 _____B7_ 五、發明説明（247 ) X1及X2乃個自爲Η或鹵基，最好爲F ; X爲2至6之整數，最好爲3至5，且（CH2)X可 任被1 ，2或3個相同或互異之取代基（烷基或鹵基）取 代；且 115$爲雜芳基，芳基，雜環烷基或環烷基，每個R5SIC 基團乃任被1 ，2，3或4個可相同或互異之下文所述取 代基所取代；其 包括式I化合物之哌啶N -氧化物，亦即 〆〇 、氏1 ;且 包括其製藥學上可接受性鹽諸如鹼金屬鹽諸如鋰，鈉 或鉀等，鹼土金屬諸如鈣或鎂等，以及鋅或鋁及其它陽離 子諸如銨，膽鹼，二乙醇胺，乙撐二胺，特丁胺，特辛胺 ，脫氫松香胺，以及製藥學上可接受性陰離子諸如氯離子 ，溴離子，碘離子，酒石酸鹽，乙酸鹽，甲烷磺酸鹽，馬 來酸鹽，琥珀酸鹽，戊二酸鹽，及天生胺基酸諸如精胺酸 ，賴胺酸，丙胺酸等之鹽類，以及其前藥酯。 R5"基團可被1，2，3或4個取代基所取代，包括 (1) 鹵素諸如Cj^，F，CF3及I。 (2) 雜芳基，包括單環或雙環系統，其包括1 ，2 或3個雜原子（雜原子爲S，N及/或0)，且其於環或 環系統中包含2至10個碳，諸如 (請先閲讀背面之注意事項再填寫本頁)〇 Where Z is a key, 0 or S; This paper size is applicable to China National Standard (CNS) A4 specification (21.0X297 mm) _ 249 (Please read the precautions on the back before filling this page). 41 ^ 衣 · 486469 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, A7 _____B7_ V. Description of Invention (247) X1 and X2 are self-fluorene or halo groups, preferably F; X is an integer from 2 to 6, preferably 3 To 5, and (CH2) X may be substituted with 1, 2, or 3 identical or mutually different substituents (alkyl or halo); and 115 $ is a heteroaryl, aryl, heterocycloalkyl or ring Alkyl, each R5SIC group is substituted with 1, 2, 3 or 4 substituents which may be the same or different from each other as described below; it includes piperidine N-oxides of compounds of formula I, i.e. And 1; and includes its pharmaceutically acceptable salts such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metals such as calcium or magnesium, and zinc or aluminum and other cations such as ammonium, choline, diethanolamine, Ethylenediamine, tert-butylamine, tert-octylamine, dehydrorosinamine, and pharmaceutically acceptable anions such as chloride, bromide Iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of natural amino acids such as spermine, lysine, alanine, etc., and Its prodrug ester. The R5 " group may be substituted with 1, 2, 3 or 4 substituents, including (1) halogens such as Cj ^, F, CF3 and I. (2) Heteroaryl, including monocyclic or bicyclic systems, which includes 1, 2, or 3 heteroatoms (heteroatoms are S, N, and / or 0), and which contains 2 to 10 in the ring or ring system Carbon, such as (please read the notes on the back before filling this page)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）__ 250 486469 A7 B7 五、發明説明（248 )This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) __ 250 486469 A7 B7 V. Description of the invention (248)

NN

ΚΓ N (請先閱讀背面之注意事項再填寫本頁) ·«裝. 3 )雜芳基烷基，其中雜芳基乃如上所述，諸如 (CH2) (4 )環雜烷棊，其於單環或雙環系統中包括 或3個雜原子（雜原子爲S，N或0)，諸如 2 訂 經濟部中央標準局員工消費合作社印製ΚΓ N (please read the notes on the back before filling out this page) · «Pack. 3) Heteroarylalkyl, where heteroaryl is as described above, such as (CH2) (4) cycloheteroalkane, which is used in Monocyclic or bicyclic systems include or 3 heteroatoms (heteroatoms are S, N or 0), such as 2 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

N ο C •κ.N. ό 〇 基 苯 如 ;諸 基基 烷芳 \]χ 5 6 基 鹵 x—y a 被 基 烷 \1/ b 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 251 _ 486469 A7 B7 五、發明説明（ 249 ) (c广C F 3〇，（d )烷氧基 'cp3 (f ) C F 3 ，或（g)苯基取代之苯基； (7 ·)烷胺基諸如 一I一(ch2〉pcp3 — · (8)烷基（芳基）胺基諸如一 N (CH3 /CP3 —S〈 CP3 (9 )烷硫基諸如一 s -（ C' Η 2 ) p C F 3 c 6h (請先閲讀背面之注意事項再填寫本頁) s -院基N ο C • κ.N. 〇 Benzene; allyl alkane \] χ 5 6 xyl halide x—ya pentane \ 1 / b This paper size applies Chinese National Standard (CNS) A4 specification (210X297 (Mm) _ 251 _ 486469 A7 B7 V. Description of the invention (249) (c 2 CF 3 0, (d) alkoxy 'cp3 (f) CF 3, or (g) phenyl substituted phenyl; (7) ·) Alkylamino groups such as I- (ch2> pcp3 — · (8) alkyl (aryl) amino groups such as N (CH3 / CP3 —S <CP3 (9) alkylthio groups such as s-(C ' Η 2) p CF 3 c 6h (Please read the precautions on the back before filling this page) s-Yuanji

S •S-(CH2)P-S-C6H5S • S- (CH2) P-S-C6H5

O (1 0)烷氧基諸如一 〇 -（CH2) p — cf3. ,CP3 ·〇 cf3O (1 0) alkoxy such as -0- (CH2) p — cf3., CP3 · 〇 cf3

〇C H 經濟部中央標準局員工消費合作社印製 )環烷基諸如環己基； 2)芳氧基諸如 (1 3 )胺基；〇C H Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs) Cycloalkyl such as cyclohexyl; 2) Aryloxy such as (1 3) amine;

Ncp3 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 252 一Ncp3 This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 252 I

Cl 486469 A7 B7 五、發明説明（25〇 ) ΓΊ 4 )芳胺基諸如Cl 486469 A7 B7 V. Description of the invention (25 °) ΓΊ 4) Aromatic amino groups such as

Cl )芳硫基諸如 ch3〇.Cl) arylthio such as ch30.

och3 och3och3 och3

(1 6 )磺基諸如（a )烷磺基，諸如. 11 cch3 (請先閲讀背面之注意事項再填寫本買)(1 6) sulfo such as (a) alkyl sulfo, such as. 11 cch3 (Please read the precautions on the back before filling in this purchase)

(b )烷氧羰基，諸如_iL *CP3 c )芳醯基，諸如 c6H5(b) an alkoxycarbonyl group, such as _iL * CP3 c) arylene, such as c6H5

d)雜芳胺羰基，諸如 • NH-CH2 -0 經濟部中央標準局員工消費合作社印製d) Heteroarylamine carbonyls such as • NH-CH2 -0 Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

CH3 )芳基烷氧羰基，諸如 • c—〇— CHjCeHs . (1 7)芳硫烷基，諸如一 CH2_S — CeH c (1 8 )雜芳胺基，諸如 N —N (CH3) — CH2—^一》 CP3 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 253 - 486469 A7 B7 五、發明説明（251 ) (19)芳基烷氧基，諸如 2 0 )雜芳硫基，諸如 cp3 (2 1 )雜芳氧基，諸如 C1 | ;及 (請先閱讀背面之注意事項再填寫本頁) (2 2 )芳亞磺醯基，諸 C1 故，本發明式I *化合物包含下列結構之化合物 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 254 _ 486469 A7 B7 五、發明説明（252 ) 1; I*· X1CH3) arylalkoxycarbonyl, such as • c—0—CHjCeHs. (1 7) arylsulfanyl, such as mono-CH2-S—CeHc (1 8) heteroarylamino, such as N—N (CH3) — CH2— ^ 1 "CP3 This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) _ 253-486469 A7 B7 V. Description of the invention (251) (19) Aryl alkoxy, such as 2 0) Heteroaryl sulfur , Such as cp3 (2 1) heteroaryloxy, such as C1 |; and (please read the notes on the back before filling this page) (2 2) arylenesulfinyl, C1 Therefore, the formula I of the present invention * The compound contains the following structures: The compound printed by the Central Bureau of Standards of the Ministry of Economic Affairs and the Consumer Cooperatives printed on this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 254 _ 486469 A7 B7 V. Description of the invention (252) 1; I * · X1

II 〇II 〇

Rs&lt; jb*Rs &lt; jb *

Ic， X1Ic, X1

II ο •Rs&lt; and (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 此外，本發明亦提供預防，抑制或治療動脈粥瘤硬化 ，胰臟炎或肥胖症之方法，其中上文所述式I*化合物係 以可降低微粒體三酸甘油酯轉換蛋白質活性之量投服。 此外，本發明乃提供降低血清脂肪值，膽固醇及/或 三酸甘油酯，或抑制及/或治療高脂血症，高脂肪血症， 高脂蛋白血症，高膽固醇血症及/或高三酸甘油酯血症之 方法，其中，上述式I*化合物係以可降低微粒體三酸甘 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 255 - 486469 A 7 ____B7_ 五、發明説明（253 ) 油酯轉，·換蛋白質之活性之量投服。 (請先閲讀背面之注意事項再填寫本頁) 本文所定義之適當（CH2) x基團（其中X爲2至6 ，最好爲3至5)(其可包括烷撐，烯撐或炔撐基團）可 任包括1 ，2或3個烷基或鹵素，此外，鏈中之一個碳原 子可被氧原子，N - Η，N —烷基或N —芳基所替代。 (C Η 2) χ基團之實例包括 —CH = =CH —CH2 一 —CH2CH —CH —, 一c =c —CHa - —ch2_ 一 i? 一 , 0 一 CH2— CH2— CH2—， 0 j ch3 一 ch2c scch2 —， 1 一 C =CH —CH2 一， —(CH2)2 —, —(CH2)3 —, —(ch2)4 —, ch3II ο • Rs &lt; and (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs In addition, the present invention also provides the prevention, suppression or treatment of atherosclerosis, pancreatitis or obesity The method of the present invention, wherein the compound of formula I * described above is administered in an amount that can reduce the activity of microsomal triglyceride conversion protein. In addition, the present invention provides reducing serum fat value, cholesterol and / or triglycerides, or inhibiting and / or treating hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, and / or hypertensive Method for acid glyceride, wherein the compound of the formula I * is applied to reduce the microsomal tri-acid glycine paper standard to Chinese National Standard (CNS) A4 (210X297 mm) _ 255-486469 A 7 ____B7_ V. Description of the invention (253) The conversion of oleic esters, the amount of protein activity is taken. (Please read the notes on the back before filling out this page) Appropriate (CH2) x groups (where X is 2 to 6, preferably 3 to 5) as defined herein (which may include alkylene, alkylene or alkyne The support group) may include 1, 2, or 3 alkyl groups or halogens. In addition, one carbon atom in the chain may be replaced by an oxygen atom, N-fluorene, N-alkyl group, or N-aryl group. Examples of (C Η 2) χ groups include —CH = = CH —CH2 — —CH2CH —CH —, — c = c —CHa-—ch2_ —i? 1, 0 —CH2 — CH2 — CH2 —, 0 j ch3 one ch2c scch2 —, 1 one C = CH —CH2 one, — (CH2) 2 —, — (CH2) 3 —, — (ch2) 4 —, ch3

.1 I.1 I

—(CH2)2 —c —ch2ch2 一, 一 ch2ch —, —CH2CHCH2 一, I CH3 ch3 〇2Η5 一 chch2 —, —chch2ch2 一， 一 chchch2 —， I I || CH3 C^Hs I CH3 經濟部中央標準局員工消費合作社印製 ch3 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 256 - 486469 A7 B7 五、發明説明（254 ) Ο 0 0 ch2ch2〇— c一，— ch2ch2n— c一，- ch2ch2- n— c—, H CH3 ch3 •ch2—c—ch2 ch3— (CH2) 2 —c —ch2ch2 one, one ch2ch —, —CH2CHCH2 one, I CH3 ch3 〇2Η5 one chch2 —, —chch2ch2 one, one chchch2 —, II || CH3 C ^ Hs I CH3 Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperatives ch3 This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) _ 256-486469 A7 B7 V. Description of the invention (254) 0 0 0 ch2ch2 0 — c1, — ch2ch2n — c1 ,-Ch2ch2- n— c—, H CH3 ch3 • ch2—c—ch2 ch3

FF

，—(CHJg-，一(CH2)2 — C —CH2—， I F, — (CHJg-, one (CH2) 2 — C —CH2 —, I F

Cl •CH2—CH _CH2—，一(ch2&gt;2 —J CH3 ch3 ch3 CH—C— ? I ch3 CH2 —CH 一CH2—CH ， CH3 ch3 _CH2 — CH —CH —CH2 一， CH3 ch3 OH OCH3I I •CH — CH2CH2 — —CH-CH2CH2 , 一 CH2OCHi—, -OCH2CH2- _ch2nhch2_ ch3 (CH2)3一CF2—， 一CH2-N—CH2« -nhch2ch2- -N- CH2CH2-ch3 (請先閱讀背面之注意事項再填寫本頁) 衣· 訂Cl • CH2—CH _CH2—, one (ch2 &gt; 2 —J CH3 ch3 ch3 CH—C—? I ch3 CH2 —CH one CH2—CH, CH3 ch3 _CH2 — CH —CH —CH2 one, CH3 ch3 OH OCH3I I • CH — CH2CH2 — —CH-CH2CH2, one CH2OCHi—, -OCH2CH2- _ch2nhch2_ ch3 (CH2) 3—CF2—, one CH2-N—CH2 «-nhch2ch2- -N- CH2CH2-ch3 (Please read the notes on the back first Fill out this page again)

F I (CH2)2—C— CH2-H fH3 •(CH2〉2一 C一 CH2-H CH3 .(0¾) 2 — c — CH2 I ch3 (CH2)3 —c- ch3 或 (ch2)3·F I (CH2) 2—C— CH2-H fH3 • (CH2> 2—C—CH2-H CH3. (0¾) 2 — c — CH2 I ch3 (CH2) 3 —c- ch3 or (ch2) 3 ·

ch3 c一 I H 經濟部中央標準局員工消費合作社印製 本文單獨或作爲另一基團一部分之所謂A雜芳基#乃 如上所述。A雜芳基'團之其它實例乃示於下。ch3 c- I H Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. The so-called A heteroaryl #, alone or as part of another group, is described above. Other examples of A heteroaryl 'groups are shown below.

(丫， 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-257 _ 486469 A7 B7 五、發明説明（255 )(Yes, this paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) -257_486469 A7 B7 V. Description of the invention (255)

等Wait

R 且包括所有可能之N -氧化物衍生物。 理想之式1$化合物爲其中 Z爲一個鍵， X 1及X 2爲Η ; 爲芳基諸如苯基等，其乃被 (1 )芳基諸如苯基 ch3，入 .5,ό, (請先閱讀背面之注意事項再填寫本頁) (2 )雜芳基諸如 3 )鹵基諸如C β等所取代 經濟部中央標準局員工消費合作社印製 R 爲雜芳基諸如 其乃被(1 ) 或 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 _ 486469 A7 B7 五、發明説明（?』6 ) (2广芳硫基諸如 C1 等所取代 〇 (請先閲讀背面之注意事項再填寫本頁) 其中R 5*取代基最好位在鄰近於鍵結成||之碳之位置上。R includes all possible N-oxide derivatives. Ideally, the compound of formula 1 $ is where Z is a bond, X 1 and X 2 are Η; is an aryl group such as phenyl, etc., which is replaced by (1) aryl group such as phenyl ch3, (Please read the notes on the back before filling this page) (2) Heteroaryl groups such as 3) Halo groups such as C β, etc. are printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Or this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 486469 A7 B7 V. Description of the invention (?) 6) (2 Replaced by a wide aromatic thio group such as C1, etc. (Please read the back Note: Please fill in this page again.) Among them, the R 5 * substituent is preferably located at a position adjacent to the carbon bonded to ||.

CC

(c Η 2 ) X爲一（C Η 2 ) 4或 F —ch2— ch2—c- ch2— F . 下列實例代表本發明之其它理想具體實施例。除非另 有指定，否則所有溫度均爲°C。 注意：下列實例中所用之所謂 &gt; 急驟色層分離'乃意指於 EM工業矽膠60 (230 - 400節目）上於1〇 一 2 0 p s i氮壓下進行之色層分離法。 實例 1 * 經濟部中央標準局員工消費合作社印製 9 一〔4 一〔4 —〔 （ 〔1 ，1 一聯苯基〕一 4 一 基羰基 )胺基〕一 1 一哌啶基〕一3，3-二氟丁基〕一 N —( 2，2，2 —三氟乙基）一 9H —芴一 9 一甲醯胺，單氫 氯酸鹽___ 259 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469 A7 B7 五、發明説明（257 ) A.(c Η 2) X is one (C Η 2) 4 or F — ch2 — ch2 — c — ch2 — F. The following examples represent other preferred embodiments of the present invention. Unless otherwise specified, all temperatures are in ° C. Note: The so-called &quot; flash layer separation &quot; used in the following examples means a color layer separation method performed on EM Industrial Silicone 60 (230-400 programs) under a nitrogen pressure of 10-20 ps. Example 1 * Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 9-[4-[4 — [([1,1 -biphenyl]-4 -carbonylcarbonyl) amino] -1 -piperidinyl] -3 ， 3-difluorobutyl] -N — (2,2,2-trifluoroethyl) —9H — 芴 -9 monomethylamine, monohydrochloride ___ 259-This paper applies Chinese national standards (CNS) A4 specification (210X297 mm) 486469 A7 B7 V. Description of the invention (257) A.

C OEt (請先閲讀背面之注意事項再填寫本頁)C OEt (Please read the notes on the back before filling this page)

0H0H

經濟部中央標準局員工消費合作社印裝 | (5·18克，33·6毫莫耳 )，乙醯氯（5· 2毫升）及乙酸酐（5. 2毫升）之混 合液於氬下加熱至5 0 °C 1小時。再將反應冷卻及蒸發。 令餘留物溶於乙醇（2 0毫升）中，再於室溫下，於氬下 攪拌。16小時後，將溶液蒸發，令餘留物再溶於乙醚中 ，繼而將溶液乾燥（硫酸鈉），即得無色油狀之標題化合 物，5 · 9 1克，9 7%物料平衡度。化合物乃予使用而 不必更進一步純化。 B. OEt ΟPrinted by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs | (5.18 g, 33.6 mmol), a mixture of acetyl chloride (5.2 ml) and acetic anhydride (5.2 ml) was heated under argon To 50 ° C for 1 hour. The reaction was cooled and evaporated. The residue was dissolved in ethanol (20 ml) and stirred at room temperature under argon. After 16 hours, the solution was evaporated, the residue was redissolved in ether, and the solution was dried (sodium sulfate) to obtain the title compound as a colorless oil, 591 g, 9 7% mass balance. The compound was used without further purification. B. OEt Ο

OH 於室溫下，於氬下，將甲硼烷一甲基硫複合物（ 本紙張尺度適用中國國家標準（CNS ) A4規格（210x 297公釐）一 260 - 486469 A7 ___ _B7__ 五、發明説明（258 ) 1 · 2’·5毫升，13 · 2毫莫耳）之二氯甲烷（14毫升 )溶液加至已攪拌之第Α部化合物（1 · 82克， 10 · 0毫莫耳）之四氫呋喃（10毫升）溶液中。再令 反應迴流。24小時後，將反應冷卻，將甲醇（20毫升 )加入，繼而再度迴流。1小時後，將過量溶劑於大氣壓 下蒸餾。再將餘留物於減壓下球管對球管式蒸餾，即得無 色油狀之標題化合物（1 . 45克，86%)。 c.OH at room temperature, under argon, the borane-methylsulfur compound (this paper size applies the Chinese National Standard (CNS) A4 size (210x 297 mm)-260-486469 A7 _ _B7__ V. Description of the invention (258) 1 · 2 '· 5 ml, 1 · 3 mmol) of methylene chloride (14 ml) was added to the stirred part A compound (1.82 g, 1 · 0 mmol) Tetrahydrofuran (10 ml). The reaction was refluxed. After 24 hours, the reaction was cooled, methanol (20 ml) was added, and then refluxed again. After 1 hour, the excess solvent was distilled under atmospheric pressure. The residue was subjected to bulb-to-bulb distillation under reduced pressure to obtain the title compound (1.45 g, 86%) as a colorless oil. c.

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於室溫下，於氬下，將Ph2tBuSiCj?( 2 · 6毫升，9 · 2毫莫耳）及咪唑（1 . 4克，21毫 莫耳）加至已攪拌之第B部化合物（1 · 40克， 8 · 33毫莫耳）之二甲基甲醯胺（10毫升）溶液中。 2小時後，使用水令反應中止，再以乙醚萃取三次。而後 將有機萃取液結合，乾燥（硫酸鈉）及蒸發以得棕色油狀 物。再藉於矽膠上進行急驟色層分離（5 X 2 0公分柱， 2 :7二氯甲烷/己烷）而予以純化，即得無色油狀之標 題化合物（1 · 83克，54%)。D.(Please read the precautions on the back before filling this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed Ph2tBuSiCj? (2.6 ml, 9 · 2 mmol) and imidazole at room temperature and under argon. (1.4 g, 21 mmol) was added to a stirred solution of Part B compound (1.40 g, 8.33 mmol) in dimethylformamide (10 ml). After 2 hours, the reaction was stopped with water and extracted three times with ether. The organic extracts were combined, dried (sodium sulfate) and evaporated to give a brown oil. It was then purified by flash chromatography on a silica gel (5 x 20 cm column, 2: 7 dichloromethane / hexane) to obtain the title compound (1.83 g, 54%) as a colorless oil. D.

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 26ι 一 486469 Α7 Β7 經濟部中央標準局員工消費合作社印製 五、發明説明（ 259 ) 於宝溫下，於氬下，從氫硼化鋰溶液（1 . 2毫升， 2 · 4毫莫耳，2莫耳濃度之四氫呋喃液）加至已攪拌之 第C部化合物（1 · 73克，4 · 26毫莫耳）之四氫呋 喃（5毫升）溶液中。1 6小時後，使用飽和碳酸氫鈉溶 液令反應混合物之反應中止，再以乙酸乙酯萃取三次。而 後將有機萃取液乾燥（硫酸鈉）及蒸發，即得無色油狀之 標題化合物（1 · 5 1克，9 7 % )。此化合物乃用於接 續反應中不而必更進一步純化。 _E. | 〇CH2OCH2Ph I OSiPhjtBu ...... &quot; &quot; I 於1 0°C下，於氬下，將笮氧基甲基氯（Borneo )(〇·7毫升，4.9毫莫耳）一次地加至已攪拌之第 D部化合物（1 · 50克，4 · 12毫莫耳）之二異丙基 乙胺（5毫升）溶液中。沈澱物乃於1 0分鐘內開始形成 。1小時後，將己烷加至反應混合物中，再將所得漿液以 1 0 %氫氯酸（2 0毫升）清洗並以水清洗一次。而後將 有機層乾燥（硫酸鎂）及蒸發以得淡黃色油狀物。於矽膠 上藉急驟色層分離法（5x20公分柱，2 : 3二氯甲烷 /己烷）予以純化，即得無色油狀之標題化合物（ 1 · 7 7 克，8 9 % )。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）-262 - 486469 A7 B7 五、發明説明（26〇 )This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 26ι 486469 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (259) Under Bao Wen, under argon, from Lithium borohydride solution (1.2 ml, 2.4 mmol, 2 mole tetrahydrofuran solution) was added to the stirred tetrahydrofuran of the compound of Part C (1.73 g, 4.26 mmol) (5 ml) solution. After 16 hours, the reaction of the reaction mixture was stopped using a saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The organic extract was dried (sodium sulfate) and evaporated to give the title compound (1.51 g, 97%) as a colorless oil. This compound was used in subsequent reactions without further purification. _E. | 〇CH2OCH2Ph I OSiPhjtBu ...... &quot; &quot; I At 10 ° C, under argon, oxymethyl chloride (Borneo) (0.7 ml, 4.9 mmol) Add once to a stirred solution of Part D compound (1.50 g, 4.12 mmol) in diisopropylethylamine (5 ml). Precipitation began to form within 10 minutes. After 1 hour, hexane was added to the reaction mixture, and the resulting slurry was washed with 10% hydrochloric acid (20 ml) and once with water. The organic layer was then dried (magnesium sulfate) and evaporated to give a pale yellow oil. Purification by flash chromatography (5x20 cm column, 2: 3 dichloromethane / hexane) on silica gel gave the title compound (1.77 g, 89%) as a colorless oil. (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -262-486469 A7 B7 V. Description of the invention (26〇)

於室溫下，於氬下，將四丁銨化氟溶液（TBAF， 7 · 5毫升，7 · 5毫莫耳，1莫耳濃度之四氫呋喃液） 加至已攪拌之第E部化合物（1 · 72克，3 · 55毫莫 耳）之四氫呋喃（5毫升）溶液中。1小時後，使用鹽水 令反應中止，再以乙酸乙酯萃取兩次。而後將(結合之萃取 液乾燥（硫酸鈉）及蒸發。再藉於矽膠上進行急驟色層分 離法（5x12公分柱，1 : 9乙酸乙酯/二氯甲烷）予 以純化，即得無色油狀之標題化合物（774毫克，8 9 % )。 〇. 丨Add tetrabutylammonium fluoride solution (TBAF, 7.5 ml, 7.5 millimoles, 1 mol tetrahydrofuran solution) at room temperature under argon to the stirred Part E compound (1 · 72 g, 3.55 mol) in tetrahydrofuran (5 ml). After 1 hour, the reaction was quenched with brine and extracted twice with ethyl acetate. Then (the combined extract was dried (sodium sulfate) and evaporated. It was purified by flash chromatography (5x12 cm column, 1: 9 ethyl acetate / dichloromethane) on silica gel to obtain a colorless oil. The title compound (774 mg, 89%). 〇. 丨

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於室溫下，於氬下，將碘（800毫克，3 . 15毫 莫耳）之四氫呋喃（5毫升）溶液於1 〇分鐘間逐滴加至 已攪拌之第F部化合物（770毫克，3 · 13毫莫耳） ，三苯膦（826毫克，3. 15毫莫耳）及咪唑（ 47 0毫克，6 · 9毫莫耳）之四氫呋喃（1〇毫升）溶 液中。再將反應混合物以乙醚稀釋，及以飽和碳酸氫鈉（ 含5%亞硫酸氫鈉）清洗一次。而後將有機萃取液乾燥（ ^紙張尺度適用中國國家標準（CNS ) A4規格（210X297公董)~ &quot; 一 263 一 486469 A7 _____ B7___ 五、發明説明（261) 硫酸鈉0及蒸發。再藉於矽膠上進行急驟色層分離法（ (請先閲讀背面之注意事項再填寫本頁) 5 X 1 0公分柱，二氯甲烷）予以純化，即得無色油狀之 標題化合物，（935毫克，84%)。(Please read the notes on the back before filling out this page.) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the room temperature, under argon, iodine (800 mg, 3.15 mmol) tetrahydrofuran (5 ml ) The solution was added dropwise to the stirred part F compound (770 mg, 3.13 mmol), triphenylphosphine (826 mg, 3.15 mmol) and imidazole (470 mg) over 10 minutes. , 6.9 mmol) in tetrahydrofuran (10 ml). The reaction mixture was diluted with ether and washed once with saturated sodium bicarbonate (containing 5% sodium bisulfite). Then the organic extract is dried (^ paper size applies Chinese National Standard (CNS) A4 specification (210X297)) &quot; 263 486469 A7 _____ B7___ 5. Description of the invention (261) sodium sulfate 0 and evaporation. Then borrow Purification by flash chromatography on silica gel (please read the precautions on the back before filling out this page) 5 X 10 cm column, dichloromethane) and purify to obtain the title compound as a colorless oil, (935 mg, 84 %).

於氬下，於- f〇°C下，將雙（三卑基甲矽烷基）胺 化鈉（6 · 2毫升，6 · 2毫莫耳，1莫耳濃度之四氫呋 喃液）於1 0分鐘期間加至9 一芴羧酸（6 3 1毫克，Under argon, at-f0 ° C, bis (tribenzylsilyl) sodium amine (6.2 ml, 6.2 mmol, 1 mole of tetrahydrofuran solution) in 10 minutes Add to this time 1 hydrazone carboxylic acid (6 3 1 mg,

經濟部中央標準局員工消費合作社印製 3 · 0毫莫耳）之四氫呋喃（5毫升）溶液中。再將所得 漿液攪拌6 0分鐘，而後將第G部化合物（9 3 0毫克， 2 · 6 1毫莫耳）之四氫呋喃（5毫升）溶液加入。再令 反應加溫至室溫並予攪拌。48小時後，使用10 %檸檬 酸溶液令反應中止，再以乙酸乙酯萃取兩次β而後將有機 萃取液結合，乾燥（硫酸鎂）及蒸發，令油狀餘留物溶於 二氯甲烷（1 0毫升）中，再於室溫下以草醯氯入 0 · 52毫升，6 ·0毫莫耳）及二甲基甲醯胺（0 · 1 毫升）處理。1小時後，將反應蒸發，而後再溶於二氯甲 烷（5毫升）中。再於〇°C下，於氬下將此溶液於10分 鐘期間逐滴加至已攪拌之三氟乙胺氫氯酸鹽（5 0 2毫克 ，3 · 70毫莫耳）及三乙胺（1 · 12毫升，8毫莫耳 )之二氯甲烷（1 0毫升）漿液中小時後，使用1 〇 %檸檬酸溶液令反應中止，再以乙酸乙酯萃取兩次。而後 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）一 264 _ ~ 486469 Α7 Β7 五、發明説明（ 262 ) 將有檄萃取液結合，乾燥（硫酸鎂）及蒸發。再藉急驟色 層分離法（5x20公分柱，1升二氯甲烷，而後5 : 9 5乙醚/二氯甲烷）予以純化，即得 | (375毫克，47%)，繼而無色油狀之標題化合物（ 120毫克，96%)。Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (3.0 mmol) in tetrahydrofuran (5 ml) solution. The resulting slurry was stirred for 60 minutes, and then a solution of the compound G (930 mg, 2.61 mmol) in tetrahydrofuran (5 ml) was added. The reaction was warmed to room temperature and stirred. After 48 hours, the reaction was stopped using a 10% citric acid solution, β was extracted twice with ethyl acetate, and the organic extracts were combined, dried (magnesium sulfate) and evaporated to dissolve the oily residue in dichloromethane ( 10 ml), and then treated with chlorchlor chloride (0.52 ml, 6.0 mmol) and dimethylformamide (0.1 ml) at room temperature. After 1 hour, the reaction was evaporated and redissolved in dichloromethane (5 ml). This solution was then added dropwise to the stirred trifluoroethylamine hydrochloride (502 mg, 3.70 mmol) and triethylamine ( After 1 hour in a 12 ml, 8 mmol) dichloromethane (10 ml) slurry, the reaction was quenched with a 10% citric acid solution and extracted twice with ethyl acetate. Then this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)-264 _ ~ 486469 A7 B7 V. Description of the invention (262) Combined with the tritium extract, dried (magnesium sulfate) and evaporated. Purify by flash chromatography (5x20 cm column, 1 liter of dichloromethane, then 5: 95 ether / dichloromethane) to obtain | (375 mg, 47%), then the title compound as a colorless oil (120 mg, 96%).

令已攪拌之第Η部化合物（108毫克，0 · 208 毫莫耳）及2 0. %氫氧化鈀/碳（2 0 0毫克）之環己烯 (2毫升）及乙醇（5毫升）漿液於氬下迴流2小時。再 將反應冷卻，蒸發，以乙酸乙酯稀釋，乾燥（硫酸鎂）， 並通過0 · 75公尺尼龍濾器中過濾。蒸發後，即得無色 油狀之標題化合物（53毫克，64%)。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製The agitated slurry of the second compound (108 mg, 0.2208 mmol) and 20.% palladium hydroxide / carbon (200 mg) in cyclohexene (2 ml) and ethanol (5 ml) slurry Reflux under argon for 2 hours. The reaction was cooled, evaporated, diluted with ethyl acetate, dried (magnesium sulfate), and filtered through a nylon filter of 0.75 m. After evaporation, the title compound was obtained as a colorless oil (53 mg, 64%). (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

J. IJ. I

0 · 1 5毫莫耳）於2分鐘期間加至第I部化合物（ 50 · 9毫克，0 · 128毫莫耳）及吡啶（68毫升， 0 · 8毫莫耳）之二氯甲烷（1毫升）溶液中。1小時後 本紙張尺度適用中國國家標準（CNS ) Α4規格（21〇 X 297公釐） 一 265 - 486469 A7 ____B7 _ 五、發明説明（ 263 ) ’使用U莫耳濃度氫氯酸令反應中止，再以乙酸乙酯萃取 兩次。繼而將有機萃取液結合，乾燥（硫酸鎂）及蒸發， (請先閲讀背面之注意事項再填寫本頁) 即得橘色結晶固狀之標題化合物（6 8毫克，1 0 0%) 〇0 · 1 5 mmol) was added to the compound of Part I (50 · 9 mg, 0 · 128 mmol) and pyridine (68 ml, 0 · 8 mmol) in dichloromethane (1 Ml) solution. After 1 hour, the paper size will be in accordance with Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 265-486469 A7 ____B7 _ V. Description of the invention (263) 'Using a molar concentration of hydrochloric acid to stop the reaction, Extract twice with ethyl acetate. Then combine the organic extracts, dry (magnesium sulfate) and evaporate. (Please read the precautions on the back before filling this page) to get the title compound (68 mg, 100%) in the form of an orange crystal.

K. IK. I

K(l).K (l).

先將草醯氯（21毫升，280毫莫耳），繼而將數 滴二甲基甲醯胺加至2 —聯苯基羧酸（3 1 . 2克， 經濟部中夬標隼局員工消費合作杜印製 160毫莫耳）之二氯甲烷（300毫升）溶液中。反應 乃強烈起泡，再於氬下，於室溫下攪拌2小時，而後將溶 劑於真空中，於小於2 5 °C之溫度下蒸發，繼而令餘留物 溶於二氯甲烷（2 5 0毫升）中。於一 5 °C下，將此溶液 逐滴加至4 一胺基笮基哌啶（Aldrich，2 5 · 0克， 130毫莫耳）及三乙胺（46毫升，330毫莫耳）之 二氯甲烷（2 0 0毫升）溶液中。完全加入後，將反應於 彼溫下攪拌3 0分鐘。繼而將反應混合物以水清洗兩次及 以鹽水清洗一次。再將有機層乾燥（硫酸鈉），並於真空 中移去溶劑，即得淡黃色固狀之標題化合物（56 . 6克 本紙張^度適用中國國家標準（CNS ) A4規格（210X297公釐)~ — -ώΟυ ~ 486469 89. 8. ί 7 A7 B7 五、發明說明（264) ，9 5 · 4 % 產率） NH α 氧 氫 % ( ο 物 2 合 及化 } 部 耳 } 莫 1 6 ( . Κ 1 第 ， 至 升加 毫 3 7 克 6 1 1 . ( 1 烯1 己 C 環碳 將 / 鈀 化 (請先閱讀背面之注意 液小洗 溶 5 潤 } 7 醇 升 ·甲 毫 2 及 ο 拌醇 ο 攪乙 5 下以 { 溫再 醇彼， 乙於濾 之而過 } 繼中 耳 ，® 莫流te 毫迴11 ο 至ce 5 熱過 1 加通 ， 應應 克反反 5 將溫 .再令 5 οο 5 中時 事項再 本頁) 裝 訂 。而後將濾液於真空中濃縮，以得淡黃色油狀物，將此油 狀物以乙醚碾磨兩次，即得淡黃色固狀物（3 0 · 1克）Chlorchlor (21 ml, 280 mmol) was first added, and then a few drops of dimethylformamide were added to 2-biphenylcarboxylic acid (3. 1.2 g, consumed by employees of the Ministry of Economic Affairs, China Standards Administration). Cooperative printing was performed in a solution of 160 mM) in dichloromethane (300 ml). The reaction was intense foaming, and then stirred under argon at room temperature for 2 hours, and then the solvent was evaporated in vacuo at a temperature of less than 2 5 ° C, and the residue was dissolved in dichloromethane (2 5 0 ml). At 5 ° C, this solution was added dropwise to 4 -aminopyridinylpiperidine (Aldrich, 25.0 g, 130 mmol) and triethylamine (46 ml, 330 mmol) Dichloromethane (200 ml) solution. After the addition was complete, the reaction was stirred at that temperature for 30 minutes. The reaction mixture was then washed twice with water and once with brine. The organic layer was dried (sodium sulfate), and the solvent was removed in a vacuum to obtain the title compound (56.6 grams of this paper). Applicable to China National Standard (CNS) A4 (210X297 mm) ~ — -ΏΟυ ~ 486469 89. 8. ί 7 A7 B7 V. Description of the invention (264), 9 5 · 4% yield) NH α Oxygen and hydrogen% (ο Compound 2 combination and chemistry) Moh} Mo 1 6 ( Κ 1 First, add 3 milligrams to 7 grams 6 1 1. (1 ene 1 hexane C ring carbon will be / palladium (please read the note on the back of the solution small wash 5 run) 7 alcohol liter · methyl methacrylate 2 and ο Mix alcohol ο Stir B 5 times with {warm re-alcohol, B pass through the filter} Following the middle ear, ® Mo flow te back 11 ο to ce 5 heat after 1 plus pass, should be countered 5 Warm. Let 5 οο 5 times matter on this page) binding. Then the filtrate was concentrated in vacuo to obtain a light yellow oil, which was milled twice with ether to obtain a light yellow solid. (3 0 · 1 g)

經濟部智慧財產局員工消費合作社印製 於室溫下，於氬下，將第Κ部化合物（8 4毫克， 〇 . 3毫莫耳）之二甲基甲醯胺（0 . 5毫升）液加至已 攪拌之第：ί,部化合物（68毫克，0 · 126毫莫耳）之 甲苯（2毫升）溶液中。再將溶液加熱至5 0 °C，1 4小 時後，將反應冷卻，以乙醚稀釋及以飽和碳酸氫鈉溶液清 洗一次，再將有機層乾燥（硫酸鈉）及蒸發。而後於矽膠 上藉急驟色層分離法（1 X 1 0公分柱，乙酸乙酯）予以 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -267 - 486469 A7 B7五、發明説明（265 ) 純化，1即得白色泡沬狀之作爲游離鹼之標題化合物（5 7 毫克，68%)，將泡沬狀物以二氯甲烷，及0 · 1毫升 4當量濃度氫氯酸稀釋。蒸發後，即得標題化合物之氫氯 酸鹽（59毫克，熔點115 - 118 °C)。 薄層色層分離法：= 〇 · 20 (游離鹼，乙酸乙酯， 矽膠6 0 ) 質譜：（電噴霧，+離子） m / z 6 6 2 ( M + Η ) 賨例 2 $ 9 —〔4 —〔4 一〔〔 （4&gt;一 氯基一〔1，一聯苯 基〕一 2 -基）羰基〕胺基〕—1 一哌啶基〕了基〕一 Ν —(2 ，2 ，2 —三氣乙基）一9Η —荀一9 一甲醯胺’ 單氤氯酸鹽 ___ (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標隼（CNS ) Α4規格（210Χ 297公釐）一 268 - 486469 A7 B7 五、發明説明（266 )The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed the dimethylformamide (0.5 ml) solution of Part K compound (84 mg, 0.3 mmol) at room temperature under argon. Add to a stirred solution of the first and second compound (68 mg, 0.126 mmol) in toluene (2 ml). The solution was heated to 50 ° C. After 14 hours, the reaction was cooled, diluted with ether and washed once with saturated sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and evaporated. Then, on the silica gel, a rapid color layer separation method (1 X 10 cm column, ethyl acetate) was applied to this paper to apply the Chinese National Standard (CNS) A4 (210 X 297 mm) -267-486469 A7 B7 Description of the invention (265) Purified, 1 to obtain the title compound (57 mg, 68%) as a free base in the form of a white foam. The foam was made with dichloromethane and 0.1 ml of 4 equivalents of hydrogen chloride. Acid dilution. After evaporation, the hydrochloride salt of the title compound (59 mg, melting point 115-118 ° C) was obtained. Thin-layer chromatographic separation method: = 〇 · 20 (free base, ethyl acetate, silica gel 60) Mass spectrum: (electrospray, + ion) m / z 6 6 2 (M + Η) Example 2 $ 9 — 〔 4 — [4 — [[(4 &gt; -chloro- [1,1-biphenyl] -2-yl) carbonyl] amino] -1—piperidinyl] yl] —N— (2, 2, 2 —trifluoroethyl) — 9Η — 荀 -9 monomethylamine 'monochlorochlorate ___ (Please read the precautions on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 268-486469 A7 B7 V. Description of invention (266)

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 標題化合物係藉麥耶式方法藉將對位-氯苯基鎂化溴 格利雅加成至鄰位一甲氧基一苯基一1，1一二甲基異噁 唑中，再以6當量濃度氫氯酸水解而製得。 B. 9-〔4一.〔4一〔〔（4'一氯基—〔1，1/ 一聯苯基〕一 2 —基）鑛基〕一胺基〕一 1 一哌陡基〕丁 基〕一 N —（2，2，2 —三氟乙基）一 9H — 芴—9 — 甲醯胺，單氤氯酸鹽 __ 先將2莫耳濃度草醯氯（6 . 0毫升，12毫莫耳） 之二氯甲烷溶液，後將2滴二甲基甲醯胺加至第A部酸（ 2 · 0克，8 · 6毫莫耳）之二氯甲烷（35毫升）溶液 中。反應乃強烈起泡，再於氬下，於室溫下攪拌2小時， 繼而將溶劑於真空中，於低於2 5 °C之溫度下蒸發，再令 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐) - 269 - 486469 A7 _______B7___ 五、發明説明（267 ) 餘留物镕於四氫呋喃（5 0毫升）中。而後將此溶液於0 乇下逐滴加至實例11*第（：部二胺（4 · 45克， 8 · 6毫莫耳）及三乙胺（3 · 54克，35毫莫耳）之 四氫呋喃（1 5 0毫升）溶液中。將反應於熔化之冰浴中 攪拌1小時，加溫至室溫，並攪拌4 8小時。而後將反應 混合物以乙酸乙酯（2 0 0毫升）稀釋及以水清洗一次。 繼而將有機層乾燥（硫酸鎂），並於真空中移去溶劑，以 得灰白色固狀泡沬物*再將其以乙酸乙酯純化碾磨，以得 白色固狀物。 將固狀物以乙醚（1 0 0毫升）稀釋，再以1莫耳濃 度氫氯酸之乙醚液（10毫升，10毫莫耳）處理，而後 將所得白色粉末過濾。再收集固狀物，繼而於5 5。(：（ 20毫米汞柱）下乾燥過夜，即得3 · 95克（67%) 白色粉末狀之標題化合物。 熔點：140 — 150°C。 MS (ES，+ 離子）m/z 660 (M + H)； 1 C5同位素型式。 經濟部中央標隼局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) C38H37N3〇2F3C又+ H C 5之計萼分析值： 〇，63·07;Η，5·71;Ν，5·81 實測值·· C，6 2 · 7 9 ; Η，5 · 6 2 ; Ν，6 · 〇 5 〇 實例3 $ 9一〔4 一〔4 —〔 〔 〔1—(苯甲基）—2 —哌n定基〕 本紙張尺度適用中國國家標準（CNS )八4規格（210X297^釐）_ 2了(）- '--- 486469 A7 _____B7_ 五、發明説明（268 ) 羰基h胺基〕—1 —哌啶基〕丁基〕一 N -（ 2，2，2 二三氟乙某）一 9 Η —芴一 9 一甲醯胺，二氤氡酸騸(Please read the notes on the back before filling out this page) The title compound printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs has added the para-chlorophenylmagnesium bromide to the adjacent one by the Mayer method. It is prepared by hydrolyzing methoxy-phenyl-1,1-dimethylisoxazole with 6 equivalents of hydrochloric acid. B. 9- [4 a. [4 a [[(4'-chloro group-[1,1 / biphenyl]-2-group) ore group] -amino group]-1 piperidinyl] butyl Group] -N — (2,2,2-trifluoroethyl) —9H — hydrazone—9—formamidine, monoammonium chlorate __ First, 2 moles of chloramphenicol (6.0 ml, 12 millimoles) in dichloromethane, then 2 drops of dimethylformamide were added to a solution of Part A acid (2.0 g, 8.6 millimoles) in dichloromethane (35 mL) . The reaction was intense foaming, and then stirred at room temperature under argon for 2 hours, and then the solvent was evaporated in a vacuum at a temperature below 25 ° C, and the paper size was applied to the Chinese National Standard (CNS) A4 specification (210X297 mm)-269-486469 A7 _______B7___ V. Description of the invention (267) The residue is immersed in tetrahydrofuran (50 ml). This solution was then added dropwise at 0 ° F to Example 11 * (dioxamine (4.45 g, 8.6 mmol) and triethylamine (3.54 g, 35 mmol) Tetrahydrofuran (150 ml) solution. Stir the reaction in a molten ice bath for 1 hour, warm to room temperature, and stir for 4 8 hours. Then dilute the reaction mixture with ethyl acetate (200 ml) and Rinse once with water. Then dry the organic layer (magnesium sulfate) and remove the solvent in vacuo to obtain an off-white solid foamy substance * which is then purified and milled with ethyl acetate to obtain a white solid. The solid was diluted with ether (100 ml), and then treated with 1 mol of hydrochloric acid in ether (10 ml, 10 mmol), and the resulting white powder was filtered. The solid was collected, Then, it was dried at 5 5 ((20 mmHg) overnight to obtain 3.95 g (67%) of the title compound as a white powder. Melting point: 140-150 ° C. MS (ES, + ion) m / z 660 (M + H); 1 C5 isotope type. Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs (please read the first Please fill in this page if you have any questions) Analysis value of C38H37N3〇2F3C + HC 5 Analysis value: 〇, 63 · 07; Η, 5.71; ，, 5.81 Measured value ·· C, 6 2 · 7 9; Η ， 5 · 6 2; Ν, 6 · 〇5 〇 Example 3 $ 9 a [4 a [4 — [[[1-(benzyl) — 2-piperidinyl]] This paper size applies to Chinese national standards (CNS ) 8 4 specifications (210X297 ^ cent) _ 2 ()-'--- 486469 A7 _____B7_ V. Description of the invention (268) carbonyl h amino]-1-piperidinyl] butyl] -N-(2, 2,2 ditrifluoroethane) 9 Η 芴 芴 9 9 9 methylformamide, diacetate

Α. COOEtΑ. COOEt

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於氬下，將笮基溴（700毫升，5 · 7毫莫耳）逐 滴加至哌可啉酸乙酯氫氯酸鹽（1 · 0克，5 . 2毫莫耳 )及碳酸鉀（1 · 5克，11 · 4毫莫耳）之二甲基甲醯 胺（1 0毫升）漿液中。再將反應於室溫下攪拌2 . 5小 時，而後於真空中移去溶劑。繼而令餘留物分界於二氯甲 烷（1 0毫升）及水（1 0毫升）間，再將水性層以二氯 甲烷萃取（3x10毫升），而後將結合之有機層於硫酸 鈉上乾燥，再於真空中濃縮以得混濁油狀物，繼而於矽膠 (6 0克）上進行色層分離（1 0%乙酸乙酯之己烷液） 。再將純溶離份結合並予蒸發，即得無色油狀之標題化合 物（1.24 克，97%)。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 271 4^6469 A7 B7 五、發明説明（269 ) B,(Please read the notes on the back before filling out this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed under argon, and fluorenyl bromide (700 ml, 5.7 mmol) was added dropwise to pipecolic acid Ethyl hydrochloride (1.0 g, 5.2 mmol) and potassium carbonate (1.5 g, 11.4 mmol) in dimethylformamide (10 ml) slurry. The reaction was stirred for another 2.5 hours at room temperature, and then the solvent was removed in vacuo. Then divide the residue between dichloromethane (10 ml) and water (10 ml), extract the aqueous layer with dichloromethane (3x10 ml), and then dry the combined organic layer over sodium sulfate. It was then concentrated in vacuo to obtain a cloudy oil, which was then separated by chromatography on silica gel (60 g) (10% ethyl acetate in hexane). The pure soluble fractions were combined and evaporated to give the title compound (1.24 g, 97%) as a colorless oil. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) _ 271 4 ^ 6469 A7 B7 V. Description of the invention (269) B,

PhPh

N^COOH 〔丁 · HCI 將第A部化合物（600毫克，2 · 4毫莫耳）及1 當量濃度氫氧化鉀（7 · 2毫升）之二噁烷雙相混合液於 室溫下攪拌過夜，而後將反應於5 0°C下加熱2天。繼而 將反應冷卻至室溫，再使用1當量濃度氫氯酸以調整p Η 至2。將混濁混合物於真空中濃縮，而後於高度真空下泵 唧過夜。再將固狀產物與氯仿（1 0毫升）攪拌1 5分鐘 ，繼而過濾。再將濾液於真空中濃縮，即得黃色泡沫狀之 標題化合物（4 1 1毫克，6 7 % )。 c · .............———… 1N ^ COOH [Butyl · HCI Stir a biphasic mixture of the compound of Part A (600 mg, 2.4 mmol) and 1 equivalent of potassium hydroxide (7.2 ml) at room temperature overnight The reaction was then heated at 50 ° C for 2 days. The reaction was then cooled to room temperature and 1 equivalent of hydrochloric acid was used to adjust pp to 2. The cloudy mixture was concentrated in vacuo and pumped under high vacuum overnight. The solid product was stirred with chloroform (10 ml) for 15 minutes, and then filtered. The filtrate was concentrated in vacuo to give the title compound (41 1 mg, 67%) as a yellow foam. c · .............————… 1

經濟部中央標準局貝工消費合作.&amp;,f i 於氬下，將乙基3 —（ 3 —二甲胺基）丙基碳化二亞 胺（164毫克，0 · 86毫莫耳）加至實例11*第匸 部化合物（404毫克，0 · 78毫莫耳），第Β部化合 物（200毫克，0.78毫莫耳），羥基苯並三唑（ 105毫克，0 · 78毫莫耳）及4 一甲基嗎啉（300 毫升，2 · 7毫莫耳）之二氯甲烷（3毫升）混合液中。 再將反應於室溫下攪拌2 4小時，以二氯甲烷（2 0毫升Cooperation with Shellfish Consumers, Central Bureau of Standards, Ministry of Economic Affairs. &Amp;, fi Under argon, add ethyl 3- (3-dimethylamino) propylcarbodiimide (164 mg, 0.886 mmol) to Example 11 * Compound VII (404 mg, 0.78 mmol), Compound B (200 mg, 0.78 mmol), hydroxybenzotriazole (105 mg, 0.78 mmol) and 4 Monomethylmorpholine (300 ml, 2.7 mmol) in a mixture of dichloromethane (3 ml). The reaction was stirred at room temperature for 2 4 hours, followed by dichloromethane (20 ml

本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）—2*72 - 486469 Α7 Α7 Β7 五、發明説明（27〇 ) (請先閲讀背面之注意事項再填寫本頁) )稀釋及以飽和碳酸氫鈉溶液（5毫升）清洗。而後將有 機層以水（2 X 5毫升）清洗，再於硫酸鈉上乾燥。蒸發 後可得黃色膠狀物，再藉於矽膠（5 0克）上進行急驟色 層分離（4%甲醇之二氯甲烷液）予以純化。而後將純溶 離份結合並予蒸發以得無色油狀物。令所得產物溶於甲醇 (1毫升）中，再將氫氯酸之乙醚溶液（1 · 1莫耳濃度 * 1 · 1毫升）加入。而後將反應於室溫下攪拌10分鐘 ，繼而蒸發至乾。再將產物於真空爐（5 5°C，24小時 )中乾燥，即得白色固狀之標題化合物（302毫克， 5 4%)。 熔點· 1 6 1 - 1 6 5 °C。 MS (ES，+ 離子）：647 (M + H) 分析.C38H47C i?2F3N402· 1 · 5H2〇之計算值 • C，61.12;H，6.75; Ν，7·50 ;Cj?，9.50;F，7.63 實測值：C，60·. 97;Η,6«77;Ν，7·40 •，Ci2，9.18;F，7.34。 眚例4 $ N— (2，2 ，2 —三氟乙基）一 9 一〔4 一〔 4一〔〔 〔4 一（三氟甲基）〔1 ，1 一聯苯基〕一 2 —基〕羰基 〕胺基〕一 1 一哌啶基〕丁基〕一 9H -荀一 9 —甲醯胺 ，單氫氯酸鹽 __ 本紙張尺度適用中國國家標準（CNS ) Μ規格（210X297公釐）一 273 486469 A7 B7五、發明説明（2?1 )This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) —2 * 72-486469 Α7 Α7 Β7 V. Description of the invention (27〇) (Please read the precautions on the back before filling this page) Wash with saturated sodium bicarbonate solution (5 ml). The organic layer was then washed with water (2 X 5 mL) and dried over sodium sulfate. After evaporation, a yellow gum was obtained, which was then purified by flash chromatography (4% methanol in dichloromethane) on silica gel (50 g). The pure solvents were then combined and pre-evaporated to give a colorless oil. The resulting product was dissolved in methanol (1 ml), and a solution of hydrochloric acid in diethyl ether (1.1 mol concentration * 1 · 1 ml) was added. The reaction was then stirred at room temperature for 10 minutes and then evaporated to dryness. The product was dried in a vacuum oven (55 ° C, 24 hours) to obtain the title compound (302 mg, 54%) as a white solid. Melting point · 16 1-16 5 ° C. MS (ES, + ions): 647 (M + H) analysis. Calculated for C38H47C i? 2F3N402 · 1 · 5H2〇 • C, 61.12; H, 6.75; N, 7.50; Cj ?, 9.50; F, 7.63 Found: C, 60 ·. 97; Η, 6 «77; N, 7.40 •, Ci2, 9.18; F, 7.34. Example 4 $ N— (2,2,2-trifluoroethyl)-9 1 [4 1 [4 1 [[[4 1 (trifluoromethyl) [1,1 biphenyl]] 2 — Group] carbonyl group] amino group] -1 piperidinyl group] butyl group] 9H-fluorene-9-formamidine, monohydrochloride __ This paper size applies to China National Standard (CNS) M specifications (210X297) (Centi) 273 486469 A7 B7 V. Description of the invention (2? 1)

AA

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

於室溫下，於氬下，將三乙胺（2…· 8.. 〇毫升， 20 · 〇毫莫耳），二乙基胺基甲醯氯（2 β 50毫升， 19 · 5毫莫耳）及二甲胺基吡啶（100毫克）加至已 ΟΗ 攪拌之 &lt;^3 (3·08克），19·0毫莫 耳）之四氫呋喃（2 0毫升）溶液中。再將反應於5 0°C 下加熱1 8小時。而後將反應冷卻，以乙醚稀釋，以1 〇 %檸檬酸溶液，鹽水清洗並予乾燥（硫酸鎂）。再藉於矽 膠上進行急驟色層分離法（5x15公分柱，55 : 45 己烷/二氯甲烷）予以純化，即得無色油狀之標題化合物 (4.35 克，89%)。 B · F3C~^- 〇CONEt2 C02H (請先閲讀背面之注意事項再填寫本頁) 於氬氣層下，將四氫呋喃（1 0 0毫升）及N，N， 本紙張尺度適用中國國家標準（CNS〉A4規格（210X297公釐)~~' &quot; -Z ί 4 ~ 486469 經濟部中央標準局員工消費合作社印製 A7 _____B7___ 五、發明説明（272 ) N，N^_—四甲基乙撐二胺（TMEDA，4 · 4毫升， 2 9 · 2毫莫耳）加至備有滴液漏斗及溫度計之已以火焰 乾燥之三頸式燒瓶中。再將所得溶液冷卻至- 7 3 °C，而 後將另丁基鋰之己烷溶液（22 · 0毫莫耳，1 . 25莫 耳濃度，27 · 5毫莫耳）於1分鐘期間逐滴加入。30 分鐘後，將第A部化合物（5 · 9 0克，22 · 6毫莫耳 )之四氫呋喃（2 0毫升）溶液於2 0分鐘期間加入。另 一小時後，令乾二氧化碳氣體起泡通過溶液中3 0分鐘。 繼而移去冷卻浴，再令反應加溫至〇°C，而後使用1 〇% 檸檬酸溶液令此混濁溶液之反應立即中止，再以乙酸乙酯 萃取兩次，並予乾燥（硫酸鎂）及蒸發，即得白色固狀之 標題化合物，熔點124 - 126 °C (5 · 88克，85 % )。 c.%一^-〇H ! co2h 於氬下，將第B部化合物（2 · 28克，7 . 47毫 莫耳）之6莫耳濃度氫氯酸漿液（2 5毫升）加熱至迴流 1小時。再將反應冷卻，以水稀釋，並予清洗及過濾。令 此潮濕濾塊溶於乙酸乙酯中，再予以乾燥（硫酸鎂）及蒸 發*即得白色固狀之標題化合物（1 · 52克，99%) ，熔點 148 — 149 °C» (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 275 486469 經濟部中央標準局員工消費合作社印製 A7 ___B7____ 五、發明説明（273 ) ^' D · OMe C02H 於氬下，於室溫下，將碳酸鉀（2 . 8克，20毫莫 耳）加至已攪拌之第C部化合物（1 . 50克，7 . 28 毫莫耳）之二甲基甲醯胺（2 0毫升）溶液中，再將漿液 加熱至50 °C，而後將硫酸二甲酯（1 · 9毫升，20毫 .莫耳）加入。1小時後，使用1 0 %檸檬酸溶液（2 0毫 升）令反應混合物之反應中止，再以乙醚萃取兩次。繼而 將結合之萃取液以水清洗，乾燥（硫酸鎂）及蒸發以得無 色油狀之標題化合物之甲酯（1 · 71克，.100%)。 令此油狀物溶於四氫呋喃（1 0毫升）中，再將3莫 耳濃度氫氧化鈉溶液（1 0毫升）加入，而後將混合物於 氬下加熱至迴流1小時，繼而將溶液冷卻，倒至冷1莫耳 濃度氫氯酸中，再以二氯甲烷萃取兩次。而後將萃取液結 合，乾燥（硫酸鎂）.及蒸發，即得白色固狀之標題化合物 (1.45 克，91%)，熔點 105 — 107 °C。 Ε·F3C~O&quot;0Me I1 於室溫下，將草醯氯（1 · 00毫升，11 · 5毫莫 耳）及二甲基甲醯胺（5 0毫升）加至被Drierite填充管 保護之已攪拌之第B部化合物（1 · 40克，6 · 36毫 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 276 - ► 486469 A7 _____B7_五、發明説明（274 ) 莫耳尸之二氯甲烷（1 〇毫升）溶液中。2小時後，將溶 液蒸發，令之再溶於二氯甲烷（20毫升）中β於氬下， 於室溫下，將三乙胺（1 · 02毫升，7。33毫莫耳） 及2 —胺基一 2 —甲基一 1—丙醇（〇 · 70毫升， 7 · 3 3毫莫耳）先後加至此溶液中。放熱而導致橘色溶 液產生。1 3小時後，將反應混合物以二氯甲烷稀釋，以 1 0%檸檬酸溶液清洗，並予乾燥（硫酸鎂）及蒸發，即 得白色泡沬狀之標題化合物（2 · 0 8克，.&gt; 1 0 0 %物 料平衡度）。 F. f3c (請先閱讀背面之注意事項再填寫本頁)At room temperature, under argon, triethylamine (2 ... · 8 .. 0 ml, 20 · 0 mmol), diethylaminoformamidine chloride (2 β 50 ml, 19.5 mmol) Ear) and dimethylaminopyridine (100 mg) were added to a solution of &lt; ^ 3 (3.08 g), 19.0 mmol) in tetrahydrofuran (20 ml) which had been stirred. The reaction was heated at 50 ° C for 18 hours. The reaction was then cooled, diluted with ether, washed with 10% citric acid solution, brine, and dried (magnesium sulfate). It was then purified by flash chromatography (5x15 cm column, 55:45 hexane / dichloromethane) on silica gel to obtain the title compound (4.35 g, 89%) as a colorless oil. B · F3C ~ ^-〇CONEt2 C02H (Please read the precautions on the back before filling in this page) Under the argon layer, add tetrahydrofuran (100 ml) and N, N. The paper size applies the Chinese national standard (CNS 〉 A4 specification (210X297mm) ~~ '&quot; -Z ί 4 ~ 486469 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____B7___ V. Description of the invention (272) N, N ^ _— tetramethylethylene Amine (TMEDA, 4 · 4 ml, 2 · 9.2 mmol) was added to a flame-dried three-necked flask equipped with a dropping funnel and a thermometer. The resulting solution was cooled to-7 3 ° C, Then a solution of butyllithium in hexane (22.0 mmol, 1.25 mmol, 27.5 mmol) was added dropwise over a period of 1 minute. After 30 minutes, the compound of Part A ( 5.90 grams, 22.6 millimoles) of tetrahydrofuran (20 ml) was added over a period of 20 minutes. After another hour, dry carbon dioxide gas was bubbled through the solution for 30 minutes. The cooling was then removed Bath, and then the reaction was warmed to 0 ° C, and then the reaction of this cloudy solution was stopped immediately with 10% citric acid solution Then, it was extracted twice with ethyl acetate, and dried (magnesium sulfate) and evaporated to obtain the title compound as a white solid, melting point 124-126 ° C (5. 88 g, 85%). C.% 一 ^ -〇H! Co2h Under argon, heat a 6 mol hydrochloric acid slurry (2.5 ml) of the compound in Part B (2.28 g, 7.47 mmol) to reflux for 1 hour. The reaction was then allowed to react again Cool, dilute with water, wash and filter. Dissolve this wet filter block in ethyl acetate, then dry (magnesium sulfate) and evaporate * to obtain the title compound (1.52 g, 99%) ), Melting point 148 — 149 ° C »(Please read the notes on the back before filling out this page) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) _ 275 486469 Employees' Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print A7 ___B7____ 5. Description of the Invention (273) ^ 'D · OMe C02H Under argon at room temperature, add potassium carbonate (2.8 g, 20 mmol) to the agitated Part C compound ( 1.50 g, 7.28 mmol) of dimethylformamide (20 ml) and the slurry was heated 50 ° C, and then added dimethyl sulfate (1.9 ml, 20 millimoles). After 1 hour, the reaction mixture was quenched with 10% citric acid solution (20 ml), and then ether was added. Extract twice. The combined extracts were washed with water, dried (magnesium sulfate) and evaporated to give the title compound as a colorless oil (1.71 g, .100%). This oil was dissolved in tetrahydrofuran (10 ml), and a 3 mol sodium hydroxide solution (10 ml) was added, and the mixture was heated to reflux for 1 hour under argon, and the solution was cooled and poured. It was cooled to 1 molar hydrochloric acid and extracted twice with dichloromethane. The extracts were combined, dried (magnesium sulfate), and evaporated to give the title compound (1.45 g, 91%) as a white solid, melting at 105-107 ° C. Ε · F3C ~ O &quot; 0Me I1 At room temperature, add chlorpyrrolidine (1,000 ml, 11.5 mmol) and dimethylformamide (50 ml) to a protective tube filled with Drierite. Part B compound that has been stirred (1 · 40 g, 6 · 36 millimeters (please read the precautions on the back before filling in this page) The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 276- ► 486469 A7 _____B7_V. Description of the invention (274) Morse's dichloromethane (10 ml) solution. After 2 hours, the solution was evaporated and re-dissolved in dichloromethane (20 ml). Under argon at room temperature, triethylamine (1.02 ml, 7.33 mmol) and 2-amino-2-methyl-1-propanol (0.70 ml, 7.33 3 Millimoles) were added to this solution successively. Exothermic heat caused an orange solution. After 13 hours, the reaction mixture was diluted with dichloromethane, washed with a 10% citric acid solution, dried (magnesium sulfate) and evaporated. To obtain the title compound in the form of a white foam (2.08 g,. &Gt; 100% material balance). F. f3c (please read the back first (Please fill out this page again)

經濟部中央標準局員工消費合作社印製 將亞硫醯氯（1 · 9毫升，23.· 6毫莫耳）加至於 室溫下且被Drierite填充管保護之第E部化合物（ 2 · 0 8克）之二箄甲烷（20毫升）溶液中。再將溶液 攪拌2小時，而後以二氯甲烷稀釋，再倒至1:1冰及飽 和碳酸氫鈉溶液之混合物中，繼而使用1莫耳濃度氫氧化 鉀溶液以調整水性層之p Η至8，再以二氯甲烷萃取兩次 。而後將有機萃取液結合，乾燥（硫酸鈉）及蒸發。再藉 於矽膠上進行急驟色層分離法（5x10公分柱，1:9 乙酸乙酯/二氯甲烷）予以純化，即得白色固狀之標題化 合物（1 · 56克，由第D部化合物起始獲得90%產率 )，熔點 5 5 - 5 7 °C。 i紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 2了了 - 486469 A7 B7Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, Part E compound (2 · 0 8) added thionyl chloride (1.9 ml, 23. · 6 mmol) to room temperature and protected by a Drierite filled tube G) bis methane (20 ml) solution. The solution was stirred for another 2 hours, then diluted with dichloromethane, and then poured into a mixture of 1: 1 ice and saturated sodium bicarbonate solution, and then a 1 molar potassium hydroxide solution was used to adjust the p 层 of the aqueous layer to 8 , And extracted twice with dichloromethane. The organic extracts were combined, dried (sodium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (5x10 cm column, 1: 9 ethyl acetate / dichloromethane) to obtain the title compound as a white solid (1.56 g, starting from the compound in Part D). 90% yield was obtained), melting point 5 5-5 7 ° C. i Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 2 up-486469 A7 B7

五、發明説明（275) G. F3CV. Description of Invention (275) G. F3C

於0°C下，於氬下，將苯基鎂化溴溶液（1 · 7毫升 ’ 3莫耳濃度之乙醚液’ 5 · 1毫莫耳）於5分鐘期間加 至已攪拌之第F部化合物（1 · 17克，4 · 28毫莫耳 )之四氫呋喃（1 0毫升）溶液中。攪持另.1 0分鐘後， 移去冰浴，再令反應於室溫下攪拌。2小時後，使用飽和 氯化銨溶液令反應中止，再以乙酸乙酯萃取兩次。繼而將 萃取液結合，乾燥（硫酸鈉）及蒸發以得棕色油狀物。再 藉於矽膠上進行急驟色層分離法（5 X 1 5公分柱， 0 · 5升己烷，而後二氯甲烷）予以純化，即得無色油狀 之標題化合物（1 · 3 6克，100%)。Add a phenylmagnesium bromide solution (1.7 ml of '3 mol ether solution' 5.1 ml mol) at 0 ° C under argon over 5 minutes to the stirred part F A solution of the compound (1.17 g, 4.28 mmol) in tetrahydrofuran (10 ml). After stirring for another 10 minutes, the ice bath was removed and the reaction was allowed to stir at room temperature. After 2 hours, the reaction was stopped with a saturated ammonium chloride solution and extracted twice with ethyl acetate. The extracts were combined, dried (sodium sulfate) and evaporated to give a brown oil. Purification by flash chromatography on a silica gel (5 X 1 5 cm column, 0.5 liters of hexane, then dichloromethane) to obtain the title compound as a colorless oil (1.36 g, 100 %).

co2h (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 將第G部化合物（1 . 25克，3 . 91毫莫耳）之 6莫耳濃度氫氯酸（2 5毫升）漿液加熱至迴流1 3小時 ，再將反應混合物冷卻，而後以二氯甲烷萃取兩次。繼而 將萃取液結合，乾燥（硫酸鎂）及蒸發。再藉於矽膠上進 行急驟色層分離法（5 X 1 5公分柱，乙酸乙酯）予以純 化，即得白色固狀之標題化合物（395毫克，38%) ，熔點 12 0 — 122 °C。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）__ 278 486469 A7 B7五、發明説明（276 ) •HCI MσΝco2h (Please read the notes on the back before filling out this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a 6 Molar concentration of hydrochloric acid in the G compound (1.25 g, 3.91 mmol) (25 ml) The slurry was heated to reflux for 13 hours. The reaction mixture was cooled and then extracted twice with dichloromethane. The extracts were combined, dried (magnesium sulfate) and evaporated. Purify by flash chromatography (5 X 1 5 cm column, ethyl acetate) on silica gel to obtain the title compound (395 mg, 38%) as a white solid with a melting point of 12 0 — 122 ° C. This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) __ 278 486469 A7 B7 V. Description of the invention (276) • HCI MσΝ

經濟部中央標準局員工消費合作社印製 將已被Drierite填充管保護之第Η部化合物（3 8 Ο 毫克，1 · 43毫莫耳）之亞硫醯氯(3毫升）溶液於室 溫下攪拌。2小時後，將反應蒸發，而後由二氯甲烷中再 蒸發。令半固狀餘留物溶於二氯甲烷（5毫升）中，再於 0 °C下，於氬下，逐滴加至實例1 1 *第C部化合物（ 816毫克，1·57毫莫耳），三乙胺（〇·7毫升， 5毫莫耳）及二甲胺基吡啶（50毫克，0 · 4毫莫耳） 之10毫升二氯甲烷溶液中，待完全加入後，將反應加溫 至室溫並攪拌3小時，繼而將反應混合物以乙酸乙酯稀釋 ，以飽和碳酸氫鈉溶液清洗一次，再予乾燥（硫酸鈉）及 蒸發。而後藉於矽膠上進行急驟色層分離法（5 X I 5公 分柱，3 : 1 7己烷/乙酸乙酯）予以純化，即得白色泡 沬狀之標題化合物（游離鹼形式，6 40毫克，6 5%) 。令此泡沫狀物溶於二氯甲烷（5毫升）中，再以4莫耳 濃度氫氯酸之二噁烷液（0 · 3毫升）處理。蒸發後，即 得氫氯酸鹽形式之標題化合物（670毫克），熔點 1 2 9 - 1 3 4 0C。 質譜：（電噴霧，+離子） 氏張尺度適用中國國家標準（CNS〉A4規格^10X297公釐） (請先閲讀背面之注意事項再填寫本頁) 486469 A7 __ B7 五、發明説明（277 ) m / z，’· 6 9 4 ( Μ + Η )。 實例5 * 9 一〔4 一〔4 一〔 〔2 —氯基一 5 -(三氟甲基）苯醯 〕胺基〕一1 一哌啶基〕丁基〕一 Ν -（2，2，2 -三 氟乙基）一 9 Η —窃一9 一甲崎胺，Ν —氣化物 _ (請先閲讀背面之注意事項再填寫本頁)Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, a solution of the thionine compound (3 8 0 mg, 1.43 mmol) protected by a Drierite filling tube, and stirred at room temperature. . After 2 hours, the reaction was evaporated and then evaporated again from dichloromethane. The semi-solid residue was dissolved in dichloromethane (5 ml) and added dropwise to Example 1 1 at 0 ° C under argon. * Part C compound (816 mg, 1.57 mmol) Ear), triethylamine (0.7 ml, 5 mmol) and dimethylaminopyridine (50 mg, 0.4 mmol) in 10 ml of dichloromethane. After the addition is complete, the reaction is The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was then diluted with ethyl acetate, washed once with saturated sodium bicarbonate solution, dried (sodium sulfate) and evaporated. It was then purified by flash chromatography on a silica gel (5 XI 5 cm column, 3: 17 hexane / ethyl acetate) to obtain the title compound (free base form, 6 40 mg, in white foam). 6 5%). This foam was dissolved in dichloromethane (5 ml) and treated with 4 moles of hydrochloric acid in dioxane (0.3 ml). After evaporation, the title compound (670 mg) was obtained in the form of a hydrochloride salt, melting at 1 2 9-1 3 4 0C. Mass spectrometry: (Electrospray, + ion) Applicable to Chinese National Standard (CNS> A4 size ^ 10X297mm) for scales (Please read the notes on the back before filling this page) 486469 A7 __ B7 V. Description of the invention (277) m / z, '· 6 9 4 (Μ + Η). Example 5 * 9-[4-[4-[[2-Chloro-5-(trifluoromethyl) phenylhydrazone] amine]-1-piperidinyl] butyl]-N-(2, 2, 2 -trifluoroethyl)-9 Η-steal 9-methylazine, N-gaseous_ (Please read the precautions on the back before filling this page)

經濟部中央標準局員工消費合作社印製 將3 5 %過乙酸之乙酸溶液（3 · 7毫升，1 5毫莫 耳）加至實例111*胺游離鹼（8 · 50克，13 · 0 毫莫耳）之二氯甲烷（3 5毫升）溶液中。1小時後，將 另3 · 7毫升過乙酸溶液加入（15毫莫耳）。再將反應 混合物於室溫下攪拌1 6小時，以甲苯（2 0 0毫升）稀 釋，再將內容物汽提，繼而將餘留物泵唧成恆定重。將無 色殘留物以氯仿/甲醇（100毫升，9 : 1)稀釋，再 濃縮以得灰白色固狀泡沬物，而後將其由（10 : 1 ， 1 〇毫升）二氯甲烷/甲醇溶液中予以再結晶。物料產量 爲2 · 3克，母液則藉於矽膠上進行柱色層分離法並以7 :9 3甲醇/二氯甲烷洗提而予以純化，以得4 · 2克純 物料。將固狀物結合後，即得6 · 5克（75%)白色固 本紙張尺度通用中國國家標準（CNS ) Α4規格（210X297公釐）_ 280 _ 486469Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, adding 35% peracetic acid in acetic acid (3.7 ml, 15 mmol) to Example 111 * Amine Free Base (8.50 g, 13.0 mmol) Ear) in dichloromethane (35 ml). After 1 hour, another 3.7 ml of a peracetic acid solution was added (15 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with toluene (200 ml), the contents were stripped, and the residue was pumped to constant weight. The colorless residue was diluted with chloroform / methanol (100 ml, 9: 1), and concentrated to obtain an off-white solid foam, which was then added from a solution of (10: 1, 10 ml) dichloromethane / methanol. re-crystallize. The yield of the material was 2.3 g. The mother liquor was purified by column chromatography on silica gel and eluted with 7: 9 3 methanol / dichloromethane to obtain 4.2 g of pure material. 6.5 g (75%) white solid after combining the solids. The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 280 _ 486469

經濟部中央標準局員工消費合作社印製 A7 ___ B7_ 五、發明説明（278 ) 狀之標囁化合物。 熔點：1 3 1 — 1 3 6 °C ;物料繼而再固化： 熔點：198 - 200 °C分解、 MS (ES，+ 離子）m/e 6 6 8 ( M + Η )。單氯 基同位素型式。 分析· C33H32N303FeC 5 + Η20 之計算值： C，57.77;H，5.00;N，5.78 ;C 芡，5 · 0 6 實測值：C，57.44;H，5.11;N，5.78 ;C 又，5 · 0 6。 實例ft A * N —（2，2，2 —三氟乙基）一 9 一〔4 一〔4一〔〔 〔4&gt; 一（三氟甲基）〔1 ，1 一聯苯基〕一 2 —基〕羰 基〕胺基〕一 1 一哌啶基〕丁基〕一 9H —芴一 9 一甲醯 胺，N -氧化物Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___ B7_ V. The invention's description (278) of the standard compound. Melting point: 1 3 1 — 1 3 6 ° C; the material then solidifies again: Melting point: 198-200 ° C decomposition, MS (ES, + ion) m / e 6 6 8 (M + Η). Monochloro isotope pattern. Analysis · Calculated values for C33H32N303FeC 5 + Η20: C, 57.77; H, 5.00; N, 5.78; C 芡, 5 · 0 6 Found: C, 57.44; H, 5.11; N, 5.78; C, 5 · 0 6. Example ft A * N — (2,2,2-trifluoroethyl) —9— [4— [4 — [[[4 &gt;—( trifluoromethyl) [1,1—biphenyl]] — 2 —Yl] carbonyl] amino] -1 1 piperidinyl] butyl] 9H —fluorene-9 methylformamide, N-oxide

將實例10A*化合物（200毫克，0 . 274毫 莫耳）之二氯甲烷（5毫升）溶液加至0°C之飽和碳酸氫 鈉溶液（5毫升）中。數分鐘後，將間位一氯基過苯甲酸 本紙張尺度適用中國國家標準（CNS )A4規格（ 210X297公釐）-281 _ (請先閲讀背面之注意事項再填寫本頁)A solution of the compound of Example 10A * (200 mg, 0.274 mmol) in dichloromethane (5 ml) was added to a saturated sodium bicarbonate solution (5 ml) at 0 ° C. After a few minutes, the meta-chloroperbenzoic acid will be used. The paper size is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) -281 _ (Please read the precautions on the back before filling this page)

486469486469

經濟部中央標準局員工消費合作社印製 A7 ____ B7 _ 五、發明説明（279 ) (6 31毫克，80%，〇 · 2 92毫莫耳）之二氯甲烷（ 2毫升）溶液加入。再將另量之間位-氯基過苯甲酸（ 23毫克，80%，〇 · 107毫莫耳）於接下來之一小 時期間分三次加入，同時令反應回至室溫。1 · 4 5小時 後，令反應混合物分界於二氯甲烷及飽和碳酸氫鈉間。再 將水性層以二氯甲烷萃取兩次，將有機柑於硫酸鈉上乾燥 ，再於真空中濃縮成無色泡沫狀物（200毫克）。餘留 物則藉急驟色層分離法（矽膠，5〇毫升），並以5 %甲 醇：二氯甲烷，後以含1%NH40H之1 0%甲醇：二 氯甲烷洗提而予以純化，即得無色固狀之標題化合物（ 151 毫克，77· 6% 產率）^ 熔點 136 - 142 °C 〔於1 1 5 π縮短〕。 = 0 · 38 (10%甲醇：二氯甲烷）。 MS (電噴霧，+ 離子）m/z 7 1 0 + ( M + Η )。 實例6 Β $ Ν — （2 ’ 2 ，2 —三氣乙基）一 9 一〔4 一 〔4一 〔〔 〔4&gt; 一（三氟甲基）〔1 ，1 一聯苯基〕一 2 -基〕羰 基〕胺基〕一 1 一哌啶基〕丁基〕一 9Η -芴一 9 一甲醯 胺_，Ν —氩化物_ 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐）_ 282 486469 A7 B7 五、發明説明（28〇 )Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ____ B7 _ V. Description of the invention (279) (6 31 mg, 80%, 0.292 mmol) in dichloromethane (2 ml) was added. Another amount of meta-chloroperbenzoic acid (23 mg, 80%, 107 107 mol) was added in three portions over the next hour, while allowing the reaction to return to room temperature. After 1.5 hours, the reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane, the organic citrus was dried over sodium sulfate, and concentrated in vacuo to a colorless foam (200 mg). The residue was purified by flash chromatography (silica gel, 50 ml) and eluted with 5% methanol: dichloromethane, followed by elution with 10% methanol: dichloromethane containing 1% NH40H. The title compound was obtained as a colorless solid (151 mg, 77.6% yield) ^ melting point 136-142 ° C [shortened at 1 15 π]. = 0 · 38 (10% methanol: dichloromethane). MS (electrospray, + ion) m / z 7 1 0 + (M + Η). Example 6 Β $ Ν— (2'2,2-trifluoroethyl)-9 1 [4 1 [4 1 [[[4 &gt; 1 (trifluoromethyl) [1, 1 biphenyl]] 2 -Yl] carbonyl] amino] -1 piperidinyl] butyl] -9Η-芴 -9 -methylamidamine_, N-argonide_ This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297) (Centimeter) _ 282 486469 A7 B7 V. Description of the invention (28)

(另一製法） 經濟部中央標準局員工消費合作社印製 將過乙酸（1 · 7毫升，3 2%之乙酸液，8 · 08 毫莫耳）加至於絕熱水浴內之實例1 〇 A *化合物（ 5 · 3克，7 · 64毫莫耳）之二氯甲烷（20毫升）溶 液中，再將另量之過乙酸（0 · 9毫升，3 2%之乙酸液 ，4 · 28毫莫耳，共12 · 3毫莫耳）於接下來之 1 ·5小時期間分三次加入。而後令反應混合物分界於二 氯甲烷及1當量濃度氫氧化鉀間，再將水性層以二氯甲烷 萃取兩次，將結合之有機相以水清洗，於硫酸鈉上乾燥， 再於真空中濃縮以得泡沬狀物（4 . 9 5克）。而後將餘 留物由熱乙醇及水中結晶以得含仍不純固體之無色固狀物 。粗製物料（5 · 5克，與以0 . 93毫莫耳實例 1 0A#化合物作爲起始之相同反應結合）可藉急驟色層 分離法（矽膠，200克），並以10%甲醇：二氯甲烷 洗提予以純化，即得無色固狀之標題化合物（3 · 5克， 5 7 %產率）。 實例7 $ 9 一〔4 一〔4 一〔 〔2 -（2 -苯並_唑基）苯醯〕胺 本紙張尺度適用中國國家標準（CNS ) Α4規格（ 210X297公釐）一 &quot; ~ (請先閲讀背面之注意事項再填寫本頁) 486469 A7 ____B7__________五、發明説明（281 ) 基〕一〜1 一哌啶基〕丁基〕一 N —（ 2，2，2 —三氟乙 基）一9H —芴一 9 一甲醯胺，N —氣化物____(Another manufacturing method) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, Example 1 〇A * Compound with peracetic acid (1.7 ml, 32% acetic acid solution, 8.08 mmol) added to an adiabatic bath (5 · 3g, 7.64mmol) in dichloromethane (20ml), and then another amount of peracetic acid (0.9ml, 32% acetic acid solution, 4.28mmol) (Total of 12.3 millimoles) was added in three portions over the next 1.5 hours. The reaction mixture was then delimited between dichloromethane and 1 equivalent of potassium hydroxide. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated in vacuo. In order to get bubbly (4.95 g). The residue was then crystallized from hot ethanol and water to obtain a colorless solid with still impure solids. The crude material (5.5 g, combined with the same reaction starting with 0.93 mmol of Example 10A # compound) can be obtained by flash chromatography (silica gel, 200 g), and 10% methanol: two Methyl chloride was eluted and purified to give the title compound as a colorless solid (3.5 g, 57% yield). Example 7 $ 9 One [4 One [4 One [[2-(2 -benzo_azolyl) phenylhydrazone] amine) The paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm) one &quot; ~ ( Please read the precautions on the back before filling this page) 486469 A7 ____B7__________ V. Description of the invention (281) Group]-1-Piperidinyl] Butyl]-N — (2, 2, 2 — trifluoroethyl ) A 9H — 芴 9 a methylamine, N — gaseous ____

經濟部中央標準局員工消費合作社印製 將實例9*化合物（游離鹼，14 · 589克， 21 · 3毫莫耳）之二氯甲烷（約300毫升）溶液於室 溫下以4 4 0毫升3 過乙酸之稀乙酸液處理。2小時 後，將另外之過乙酸溶液（1 · 2毫升）加入，再連續攪 拌1小時，而後使用飽和碳酸氫鈉令混合物之反應中止， 再將二氯甲烷層分離出。繼而將有機萃取液以半飽和氯化 鈉清洗，再予乾燥（硫酸鈉）及過濾。而後將溶液以乙酸 乙酯（約2 0 0毫升）稀釋，並令之靜置以得白色沈澱物 ，再藉過濾法收集，以乙酸乙酯及乙醚清洗，而後於真空 中乾燥，即得標題化合物（8 . 582克，校正溶劑後爲 5 5%):熔點 189 — 191 °C。 MS (ESI (M + H) + 699 ; (Μ — Η) — 697 實例8 $ 9 一〔4 一〔4 一〔 （5 —氯基一 2 —甲基苯醯）胺基〕 本紙張尺度適用中國國家標準（〇奶）八4規格（210、&gt;&lt;297公釐）_284- (請先閲讀背面之注意事項再填寫本頁) 486469 A7 ___ B7 五、發明説明（282 ) 一 1二哌啶基〕丁基〕一 N —（2，2，2 -三氟乙基） —9 Η 一芴一 9 一甲醯胺，Ν —氧化物Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. A solution of Example 9 * (free base, 14.589 grams, 21.3 millimoles) in dichloromethane (approximately 300 ml) was used at room temperature in 4 to 40 ml. 3 Diacetate treatment with peracetic acid. After 2 hours, another peracetic acid solution (1.2 ml) was added, and stirring was continued for 1 hour, and then the reaction of the mixture was stopped with saturated sodium bicarbonate, and the methylene chloride layer was separated. The organic extract was washed with half-saturated sodium chloride, dried (sodium sulfate) and filtered. The solution was then diluted with ethyl acetate (about 200 ml) and allowed to stand to obtain a white precipitate, which was collected by filtration, washed with ethyl acetate and ether, and then dried in vacuo to obtain the title. Compound (8.582 g, 5 5% after correction solvent): melting point 189-191 ° C. MS (ESI (M + H) + 699; (Μ — Η) — 697 Example 8 $ 9 One [4 One [4 One [(5-Chloro-2-Methylphenylhydrazone) Amine]] Applicable to this paper size Chinese National Standard (〇 奶) 8 4 specifications (210, &gt; &lt; 297 mm) _284- (Please read the notes on the back before filling this page) 486469 A7 ___ B7 V. Description of the invention (282) 11 Piperidinyl] butyl] -N — (2,2,2-trifluoroethyl) —9 Η 芴 芴 9 − methylamine, N — oxide

(請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 於室溫下，於氬下，將乙撐二胺碳酸酯（2 · 61克 ，1 3 · 7毫莫耳）加至已攪拌之 ^ C,-Q~ !(Please read the precautions on the back before filling out this page.) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed the room temperature, under argon, the ethylene diamine carbonate (2 · 61 g, 1 3 · 7 Millions of moles) added to the stirred ^ C, -Q ~!

C〇aH (2 · Ο 5克，12 · 0毫莫耳），實例11*第C部化 合物（6 · 22克，12 · 0毫莫耳），N —甲基嗎啉（ 3 · 30 毫升，30 · 0 毫莫耳）及 HOBt ·Η20 ( 1 · 80克，12 · 0毫莫耳）之二氯甲烷（100毫升 )漿液中。1小時內乃形成清澈之黃色溶液。3小時後， 令反應混合物分界於乙酸乙酯及飽和碳酸氫鈉溶液間。再 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 285 486469 A7 _ _B7_ 五、發明説明（283 ) 將有機笨取液以鹽水清洗，並予乾燥（硫酸鈉）及蒸發。 而後將所得固體由乙酸乙酯/己烷中予以再結晶，即得游 離鹼形式之標題化合物（6 · 56克，91%)，熔點 2 0 1 - 2 0 2 °C。令游離鹼溶於二氯甲烷（2 5毫升） 中，再以4莫耳濃度氫氯酸之二噁烷液（3毫升）處理。 蒸發後，即得氫氯酸鹽形式之標題化合物，無定形固狀（ 7· 15 克，100%)。 微量分析· C33H35C 又 F3N30 2 + H C J2 + 0.4«[2〇 + 0.2 2二噁烷之計算值： C，61·55 ;Η，5·88 ;Ν，6.36 ;C 义，1 0 · 7 2 實測值·· C，6 1 · 5 6 ; Η，5 · 8 6 ; N，6 · 2 8 ;C 5，1 0 · 9 5 ° (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 Β· !CoaH (2.5 mg, 12.0 mmol), Example 11 * Compound C (6.22 g, 12.0 mmol), N-methylmorpholine (3.30 ml , 30 · 0 mmol) and HOBt · Η20 (1.80 g, 12.0 mmol) in dichloromethane (100 ml) slurry. A clear yellow solution formed within 1 hour. After 3 hours, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 285 486469 A7 _ _B7_ V. Description of the invention (283) The organic bulk liquid is washed with brine, dried (sodium sulfate) and evaporated. The obtained solid was then recrystallized from ethyl acetate / hexane to obtain the title compound (6.56 g, 91%) in the form of a free base having a melting point of 2 1-2 2 ° C. The free base was dissolved in dichloromethane (2.5 ml) and treated with 4 moles of hydrochloric acid in dioxane (3 ml). After evaporation, the title compound was obtained in the form of the hydrochloride as an amorphous solid (7.15 g, 100%). Microanalysis · C33H35C and F3N30 2 + HC J2 + 0.4 «[2〇 + 0.2 2 Calculated value of dioxane: C, 61 · 55; H, 5.88; N, 6.36; C meaning, 1 0 · 7 2 Measured value ·· C, 6 1 · 5 6; Η, 5 · 8 6; N, 6 · 2 8; C 5, 1 0 · 9 5 ° (Please read the notes on the back before filling this page) Order economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards

d 於室溫下，於氬下，將間位-氯基過苯甲酸（ mCPBA，220 毫克，8 0%純度，1 · 05 莫耳） 於2 0分鐘期間分次加至正快速攪拌之第A部化合物（ 635毫克，1 · 00毫莫耳）及碳酸氫鈉（100毫克 ，1 · 2毫莫耳）之二氯甲烷（20毫升）漿液中。1小 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 286 _ 486469 A7 ____ B7_五、發明説明（284 ) 時後〃將反應以二氯甲烷稀釋及以飽和碳酸氫鈉溶液清洗 兩次。繼而將有機層乾燥（硫酸鎂）及蒸發。再藉於矽膠 上進行急驟色層分離法（5x1 5公分柱，3 : 17甲醇 /乙酸乙酯）予以純化，繼而令蒸發餘留物再溶於二氯甲 烷中，並通過2毫米尼龍濾器中過濾，即得白色固狀之標 題化合物（450毫克，73%)，熔點124 - 127 0C。 微量分析· C33H35C F3N30 3 1 · 5 Η 2 〇 + 〇.6EtOAc之計算值： C，61.27;H，6.22;N，6.22 ;C 又，5 · 1 1 ; F，8 . 2 1 實測值：C，6 1 · 3 3 ; H，6 · 3 8 ; N，6 · 〇 9 ;C 芡，5.19;F，8.21° 質譜··（電噴霧，+離子） m/z 614 (M + H) 〇 (請先閲讀背面之注意事項再填寫本頁) 9 例 實 經濟部中央標準局員工消費合作社印製 9 基基 C ] 9-I 基 4 啶芴 C 哌 I I Η 4 1 91 2 基甲 胺乙 3 氟 醯三 苯 I ) 2 基， 唑 2 鹽 a ，酸 並 2 氯 苯 {氫 I I 單 2 N (I 胺 义紙張尺度適用中國國家標準(CNS ) Α4規格（210X297公釐）-狀7 一 486469 A7 B7 五、發明説明（285 )d At room temperature, under argon, add meta-chloroperbenzoic acid (mCPBA, 220 mg, 80% purity, 1.05 mol) to the portion that is being rapidly stirred in 20 minutes. Part A compound (635 mg, 1,000 mmol) and sodium bicarbonate (100 mg, 1.2 mmol) in methylene chloride (20 ml). 1 The size of the small paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 286 _ 486469 A7 ____ B7_ V. Description of the invention (284) Afterwards, the reaction is diluted with dichloromethane and saturated sodium bicarbonate The solution was washed twice. The organic layer was then dried (magnesium sulfate) and evaporated. It was purified by flash chromatography (5x1 5 cm column, 3: 17 methanol / ethyl acetate) on silica gel, and the evaporation residue was redissolved in dichloromethane and passed through a 2 mm nylon filter. Filtration gave the title compound (450 mg, 73%) as a white solid, melting at 124-127 0C. Micro analysis · C33H35C F3N30 3 1 · 5 Η 2 0 + 0.66 Calculated EtOAc: C, 61.27; H, 6.22; N, 6.22; C, 5 · 1 1; F, 8. 2 1 Found: C , 6 1 · 3 3; H, 6 · 3 8; N, 6 · 〇9; C 芡, 5.19; F, 8.21 ° Mass spectrum · (electrospray, + ion) m / z 614 (M + H) 〇 (Please read the precautions on the back before filling out this page) 9 Examples printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 9 Jiji C] 9-I radical 4 pyridinium C piperazine II Η 4 1 91 2 3 Fluorotriphenyl I) 2 group, azole 2 salt a, acid 2 chlorobenzene {hydrogen II single 2 N (I amine meaning paper standard applicable to Chinese National Standard (CNS) A4 specification (210X297 mm)-shape 7 1 486469 A7 B7 V. Description of the invention (285)

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A.A.

經濟部中央標準局員工消費合作社印製 將 硫酚（ 酸（5 反應混 而後將 當量濃 萃取三 酸酸化 空中乾 9 2 %Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Mix thiophenol (acid (5

酞酸酐（7 · 1克，47 · 9毫莫耳）及2 -胺基 7 . 0毫升，8 · 2克，65 · 4毫莫耳）之冰醋 0毫升）漿液於迴流下加熱3小時。再將已冷卻之 合物倒至約4 0 0毫升冰水中以得膠黏狀沈澱物。 混合物以乙酸乙酯萃取，再將乙酸乙酯萃取液以1 度氫氯酸及水清洗。繼而將有機層以飽和碳酸氫鈉 次，再將收集之碳酸氫鹽萃取液以6當量濃度氫氯 以得沈澱物，而後藉過濾法收集，以水清洗及於真 燥，即得白色固狀之標題化合物（11 · 27克， ):熔點 188-189 °C。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 288 - (請先閲讀背面之注意事項再填寫本頁) tl 486469 Α7 Β7 五、發明説明（286 ) B·Phthalic anhydride (7.1 g, 47.9 mmol) and 2-amino group 7.0 ml, 8.2 g, 65 · 4 mmol) ice vinegar 0 ml) slurry was heated under reflux for 3 hours . The cooled mixture was poured into about 400 ml of ice water to obtain a gummy precipitate. The mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed with 1 degree hydrochloric acid and water. Next, the organic layer was saturated with sodium bicarbonate, and the collected bicarbonate extract was concentrated at 6 equivalents of hydrogen chloride to obtain a precipitate, which was then collected by filtration, washed with water, and dried to obtain a white solid. The title compound (11.27 g,): melting point 188-189 ° C. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 288-(Please read the precautions on the back before filling this page) tl 486469 Α7 Β7 V. Description of the invention (286) B ·

經濟部中央標準局員工消費合作社印袋 將第A部酸（2 · 048克，8 · 0毫莫耳）及實例 1 1*第0部二胺（3 ·960克，7 · 6 4毫莫耳）之 二氯甲烷（80毫升）漿液以1S[ —甲基嗎啉（2 · 1毫升 ’ 1 · 93克，19 · 1毫莫耳）及二甲基甲醯胺（6毫 升）處理。而後將漿液連續以ΗΟΒΤ水合物（1 .12 克，8 · 3毫莫耳）及乙撐二胺碳酸酯（1 . 630克， 8 · 5毫莫耳）處理，混合物乃於3小時內變爲均勻。4 小時後，令溶液分界於乙酸乙酯/乙醚及飽和碳酸氫鈉間 。再將有機層分離出，以水及鹽水清洗兩次，而後乾燥（ 硫酸鈉）’過濾及汽提。進行急驟色層分離法（Merck氧 化矽’ 8/92 —甲醇/二氯甲烷）後，即得白色泡沬狀 之標題化合物（5 · 369克，理論之103%，校正溶 劑後爲9 6 % )。 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇Χ297公釐）_ 2⑽_ 486469 A7 B7 五、發明説明（287 ) 1,· C·The central government bureau of the Ministry of Economic Affairs's consumer co-operative printing bag will contain the acid of Part A (2.048 g, 0.8 mmol) and Example 1 1 * Part 0 diamine (3.960 g, 7.64 mmol) Ear) of dichloromethane (80 ml) was treated with 1S [-methylmorpholine (2.1 ml '1.93 g, 19.1 mmol) and dimethylformamide (6 ml). The slurry was then continuously treated with 〇ΒΤhydrate (1.12 g, 8.3 mmol) and ethylenediamine carbonate (1.630 g, 8.5 mmol). The mixture changed within 3 hours. For uniform. After 4 hours, the solution was delimited between ethyl acetate / ether and saturated sodium bicarbonate. The organic layer was separated, washed twice with water and brine, and then dried (sodium sulfate) 'filtered and stripped. Flash chromatography (Merck's Silica '8 / 92-methanol / dichloromethane) was used to obtain the title compound as a white foam (5.369 g, 103% of theory, and 96% after correcting the solvent). ). (Please read the precautions on the back before filling this page) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇 × 297 mm) _ 2⑽_ 486469 A7 B7 V. Description of the invention (287) 1, · C ·

經濟部中央標隼局員工消費合作社印製 令第B部化合物（游離鹼，5 · 254克，校正溶劑 後爲7 · 16毫莫耳）溶於約2 5毫升1，. 4 一二噁烷中 ，再於室溫下以2 . 2毫升4當量濃度氫氯酸之1，4 一 二噁烷液處理。而後邊快速迴盪邊將所得均勻混合物經由 套管加至約3 5 0毫升乙醚中。再將沈澱物藉過濾法收集 ，以乙醚清洗，於真空中，於4 5 °C下乾燥，即得白色固 狀之標題化合物（5 . 1 1 3克，經校正溶劑後爲9 5% )〇 MS(ESI) ： (M + H)+ 683; (M — H)_681。 實例1 0 A $ 9 一〔4-〔4 一〔〔 2 — (2，2，2-三氟乙氧基） 苯醯〕胺基〕一 1 一哌啶基〕丁基〕一 N- (2 ’ 2，2 一三氟乙基）一9H—芴一9一甲醯胺，單氫氯酸鹽 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-290 - 486469 A7 B7 五、發明説明（288 )Printed by the Consumer Standards of the Central Bureau of Standards of the Ministry of Economic Affairs, Part B compounds (free base, 5.254 g, 7.16 mmol after correction of the solvent) were dissolved in about 2.5 ml of 1, 4 dioxane And then treated at room temperature with 2.2 ml of a solution of 1,4-dioxane of 4 equivalent concentrations of hydrochloric acid. The resulting homogeneous mixture was then cannula added to about 350 ml of diethyl ether while quickly reverberating. The precipitate was collected by filtration, washed with ether, and dried under vacuum at 45 ° C to obtain the title compound as a white solid (5.13 g, 9 5% after correction of the solvent). MS (ESI): (M + H) + 683; (M — H) _681. Example 1 0 A $ 9-[4- [4-[[2 — (2,2,2-trifluoroethoxy) phenylhydrazine] amino]-1 -piperidinyl] butyl] -N- ( 2 '2,2 Trifluoroethyl) 9H- 芴 -9-Methylamine, monohydrochloride (Please read the precautions on the back before filling this page) The paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) -290-486469 A7 B7 V. Description of the invention (288)

將草醯氯（1.8毫升，21毫莫耳） 二甲基甲醯胺加至酸 H〇OC~ 繼而將數滴Add chlorammonium chloride (1.8 ml, 21 mmol) to the acid H〇OC ~ and then add a few drops

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 (3.2 中。反應 而後將溶 餘留物溶 溶液逐滴 毫莫耳） 烷（5 0 小時，繼 。再將有 使灰白色 ，8 0 0 烷洗提而 9 1.5 化矽，5 克，1 2毫莫耳）之二氯甲烷（3 乃強烈起泡，再於氬下，於室溫下 劑於真空中，於低於2 5 °C之溫度 於二氯甲烷（50毫升）中，於一 加至實例11*第（：部二胺（5. 及三乙胺.（6· 7毫升，48毫莫 毫升）溶液中。再將反應於熔化之 而將反應混合物以二氯甲烷稀釋及 機層乾燥（硫酸鈉），並將溶劑於 固狀泡沬物，將其藉急驟柱色層分 克）並以5 %甲醇：0 . 5 %氫氧 予以純化以得清澈油狀物（5 · 2 %純度）。將此油狀物藉急驟柱色 0 0克）並以3%甲醇：二氯甲烷 5毫升）溶液 攪拌2小時， 下蒸發，再令 5 °C下，將此 0 克，9 · 6 耳）之二氯甲 冰浴中攪拌1 以水清洗一次 真空中移除以 離法（氧化矽 化銨：二氯甲 3克， 層分離法（氧 洗提而再度予 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -291 - 486469 A7 ____B7_五、發明説明（289 ) 以純化1以得清澈油狀物（4 · 1 1克，6 1 · 4 %產率） 。令此油狀物（4 . 07克）溶於甲醇（2 5毫升）中， 再將1 · 1當量濃度醚性氫氯酸（8 · 0毫升）加入，而 後將溶劑於真空中移除，即得白色固狀泡沫之標題化合物 (4 · 1 7 克）。 熔點 129 — 142 °C。 MS (ESI ，+ 離子）m/z 6 9 4 ( Μ + Η ) 分析· C 3 9 Η 3 7 F 6 Ν 3 Ο 2 · Η C + Η 2 Ο 之計算值： (：，62·61;Η，5·39;Ν，5·62 實測值：C，6 2 · 4 8 ; Η，5 · 1 9 ; Ν，5 · 6 0 (請先閲讀背面之注意事項再填寫本頁) 宋 Β ο τ—I 例 實 I 基基 4 胺乙 C…氟 I醯三 9 苯 4 2 2 /ν I 2 &gt;—i u Q^_ 基 啶葱 哌 I Η 1 9 2 Ν 基 氧 乙 氣 三 2 2 鹽 ， 酸 2 氣 C 氫 I 單 經濟部中央標準局員工消費合作社印策 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）-292 一 486469 A7 B7 五、發明説明（29〇 )(Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (in 3.2. After the reaction, the residual solution was dripped in millimoles) Alkane (50 hours, then. Then dichloromethane (3 which is off-white, 8000 alkane and 9 1.5 silicide, 5 g, 12 mmol) is strongly foamed, and then under argon, it is vacuumed at room temperature under vacuum. Medium, at a temperature below 25 ° C in dichloromethane (50 ml), and add to Example 11 *: (Di-diamine (5. and triethylamine.) (6.7 ml, 48 mmol) Mo ml) solution. The reaction was melted and the reaction mixture was diluted with dichloromethane and the organic layer was dried (sodium sulfate), and the solvent was dissolved in a solid foam, which was divided into grams by flash column chromatography) It was purified with 5% methanol: 0.5% hydrogen to give a clear oil (5.2% purity). This oil was quenched by a column color of 0 g) and 3% methanol: dichloromethane. 5 ml) of the solution was stirred for 2 hours, then evaporated, and then at 0 ° C, this 0 g, 9 · 6 ears) of dichloromethane in an ice bath was stirred and washed once with water Removal in vacuum by ionization method (ammonium silicide: 3 g of dichloromethane, layer separation method (oxygen stripping and re-evaluation to this paper standard applicable to Chinese National Standard (CNS) A4 (210X297 mm) -291-486469 A7 ____B7_ V. Description of the invention (289) Purified 1 to obtain a clear oil (4.11 g, 61. 4% yield). This oil (4.07 g) was dissolved in methanol (2 5 ml), and then add 1.1 equivalents of etheric hydrochloric acid (8.0 ml), and then remove the solvent in vacuo to obtain the title compound (4.17 g) as a white solid foam. Melting point 129 — 142 ° C. MS (ESI, + ion) m / z 6 9 4 (Μ + Η) analysis · Calculated value of C 3 9 Η 3 7 F 6 Ν 3 Ο 2 · Η C + Η 2 〇 : (:, 62 · 61; Η, 5.39; Ν, 5.62 Measured value: C, 6 2 · 4 8; Η, 5 · 1 9; Ν, 5 · 6 0 (Please read the note on the back first Please fill in this page for further information) Song B ο τ—I Example I Base 4 Amine B C… Fluorine I 醯 9 9 Benzene 4 2 2 / ν I 2 &gt; —iu Q ^ _ Isopyridine I Η 1 9 2 Ν oxoethane gas 3 2 2 salt, acid 2 gas C hydrogen I single pass Department of the Central Bureau of Standards Co-op employees this policy paper printed scale applicable Chinese National Standard (CNS) Α4 size (210X297 mm) 486469 A7 B7 a -292 V. invention is described in (29〇)

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 將草醯氯（2 8. 7毫升，330毫莫耳），繼而將 二甲基甲醯胺（5滴）加至4 &gt; 一（三氟甲基）一 2 —聯 苯基羧酸（50 · 0克，190毫莫耳）之二氯甲烷（ 5 0 0毫升）漿液中。反應乃強烈起泡，再於室溫下，於 氬下攪拌2小時。所有固體均溶解且氣體停止釋出。而後 將溶劑於真空中移除，.令餘留物溶於二氯甲烷（4 0 0毫 升）中，再將此溶液逐滴加至已於冰/鹽水浴中冷卻之化 合物。 〆 νηΜ 4 —胺基一 1 一笮基哌啶（ 36 · 4毫升，180毫莫耳）及三乙胺（65 · 4毫升 ’ 4 7 0毫莫耳）之二氯甲烷（3 0 0毫升）溶液中。待 完全加入後，有許多固狀物由溶液中沈澱出。繼而將另 2 0 0毫升二氯甲烷加入。將反應於室溫下，於氬下攪拌 1 8小時，而後將反應以二氯甲烷（6 0 0毫升）稀釋， 本紙張尺度Α用中國國家標準（CNS ) Α4規格（210X297公釐）-293 - 486469 A7 B7 五、發明説明（291 ) 以飽和碳酸氫鈉清洗兩次，以鹽水清洗一次及以1當量濃 度氫氧化鉀清洗一次。再將有機層以硫酸鈉乾燥，並將溶 劑於真空中移除以得白色固狀物。而後將此固狀物由熱乙 醇（1升）中予以再結晶，並以庚烷清洗以得白色固狀物 之標題化合物（59 · 1克，75 · 6%產率），將母液 濃縮至乾，並由熱乙醇（3 0 0毫升）中予以再結晶，再 以庚烷清洗，即得第二次收成之白色固狀之標題化合物（ 12·7克，16·2%產率）。 (請先聞讀背面之注意事項再填寫本頁) • —(Please read the notes on the back before filling out this page) The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed chloramphenicol (28.7 ml, 330 mmol), and then dimethylformamide (5 Dropwise) was added to a slurry of 4 &gt; mono (trifluoromethyl) -2-biphenylcarboxylic acid (50 · 0 g, 190 mmol) in dichloromethane (500 ml). The reaction was foaming strongly, and stirred at room temperature under argon for 2 hours. All solids were dissolved and gas evolution ceased. The solvent was then removed in vacuo. The residue was dissolved in dichloromethane (400 mL) and the solution was added dropwise to the compound that had been cooled in an ice / brine bath. 〆νηΜ 4 —Amino-1,1-Aminopiperidine (36 · 4 ml, 180 mmol) and triethylamine (65 · 4 ml '4 700 mmol) in dichloromethane (300 ml ) In solution. After the addition was complete, many solids precipitated from the solution. Then another 200 ml of dichloromethane was added. The reaction was stirred at room temperature under argon for 18 hours, and then the reaction was diluted with dichloromethane (600 ml). The paper size A was in accordance with Chinese National Standard (CNS) A4 size (210X297 mm) -293. -486469 A7 B7 5. Description of the invention (291) Wash twice with saturated sodium bicarbonate, once with brine and once with 1 equivalent of potassium hydroxide. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo to give a white solid. This solid was then recrystallized from hot ethanol (1 liter) and washed with heptane to give the title compound (59.1 g, 75.6% yield) as a white solid. The mother liquor was concentrated to It was dried and recrystallized from hot ethanol (300 ml) and washed with heptane to obtain the title compound (12.7 g, 16.2% yield) as a white solid in the second harvest. (Please read the notes on the back before filling out this page) • —

訂 經濟部中央標準局員工消費合作社印製 將環己烯（150毫升，1 · 5莫耳）及20%氫氧 化鈀/碳（11 · 8克）加至第A部化合物（59 · 0克 ，130毫莫耳）之甲醇（300毫升）及乙醇（300 毫升）溶液中。再將反應於氬氣層中加熱至迴流（8 0 °C )，而後於彼溫下攪拌2.5小時，繼而令熱混合物通過 寅氏鹽中過濾，以甲醇清洗，再於真空中移去溶劑，即得 白色固狀之標題化合物（46 · 7克，99 · 6%產率） 線 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ 294 - 486469 A7 B7 五、發明説明（292 ) C.Ordered by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Cyclohexene (150 ml, 1.5 mol) and 20% palladium hydroxide / carbon (11.8 g) were added to the Part A compound (59.0 g). , 130 mmol) in methanol (300 ml) and ethanol (300 ml). The reaction was heated to reflux (80 ° C) in an argon layer, and then stirred at that temperature for 2.5 hours. Then the hot mixture was filtered through Yin's salt, washed with methanol, and the solvent was removed in vacuo. The title compound was obtained as a white solid (46 · 7 g, 99.6% yield). The size of the paper was adapted to the Chinese National Standard (CNS) A4 (210X297 mm) _ 294-486469 A7 B7. 5. Description of the invention ( 292) C.

於室溫下，於氬下，將碳酸鉀（12 . 6克，49毫At room temperature, under argon, potassium carbonate (12.6 g, 49 mmol

莫耳），繼而將 Y 化合物（依實例 1 1 *第C ( 2 )部中所述之方法製得）（2 1 · 0克， 49毫莫耳）加至已攪拌之第Β部化合物（18 · 0克， 4 9毫莫耳）之二甲基甲醯胺（1 0 0毫升）溶液中。再 將反應加熱至5 0°C，而後於彼溫下，於氬下攪拌2 4小 時，冷卻後，將反應過濾以移去碳酸鉀，繼而將濾塊以乙 酸乙酯潤洗。再令舞液分界於2 0 %庚烷之乙酸乙酯液與 水間。而後將有機層以水清洗五次及以鹽水清洗一次。再 (請先閲讀背面之注意事項再填寫本頁)Mol), and then compound Y (prepared as described in Example 1 1 * Part C (2)) (21.0 g, 49 mmol) was added to the stirred Part B compound ( 18.0 g, 49 mmol) in dimethylformamide (100 ml). The reaction was heated to 50 ° C, and then stirred at that temperature for 24 hours under argon. After cooling, the reaction was filtered to remove potassium carbonate, and the filter block was rinsed with ethyl acetate. The dance liquid was then delimited between 20% heptane in ethyl acetate and water. The organic layer was then washed five times with water and once with brine. Again (Please read the notes on the back before filling out this page)

、1T 線 經濟部中央標準局員工消費合作社印製 將有機層乾燥（硫酸鈉），並將溶劑於真空中移 褐色固狀物（30克）。繼而將此固狀物由30 2 5%乙酸乙酯之庚烷液中予以再結晶，即得灰 之標題化合物（27 · 0克，78 · 9%產率） 164 - 68 〇Ce 實例1 1 # 除以得灰 0毫升 白色固狀 。熔點 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-295 - 486469 A7 ______B7五、發明説明（293 ) 9 一〔1 一〔4 一〔 （2 —吡啶基苯醯）胺基〕一 1 一呢 啶基〕丁基〕一 N —（2，2，2 -三氟乙基）一 9H — 叛一 9 一甲醯胺，二氣氣酸鹽Line 1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Dry the organic layer (sodium sulfate) and move the solvent in vacuum to a brown solid (30 g). This solid was then recrystallized from 30 2 5% ethyl acetate in heptane to obtain the title compound (27.0 g, 78.9% yield). 164-68 〇Ce Example 1 1 # Divide to get 0 ml of white solid. Melting point The paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -295-486469 A7 ______B7 V. Description of the invention (293) 9 1 [1 1 [4 1 [(2-pyridylphenylhydrazone) amino group ]-1 -Nonidyl] butyl] -N-(2,2,2-trifluoroethyl)-9H-benzamidine

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

訂 經濟部中央標準局員工消費合作社印製 於氬下，將肆（三苯磷烷）鈀。（70 0毫克， 0 · 6毫莫耳）加至已脫氣之2 -溴基吡啶（1.9毫升 ，20毫莫耳）之乙二醇二甲基醚（60毫升）溶液中。 攪拌10分鐘後，.將2 —甲苯基硼酸（2 .9克，22毫 莫耳），繼而將碳酸氫鈉（5. 04克，60毫莫耳之 6 0毫升水液）加入，繼而將混合物加熱至迴流（約8 5 °C )，再於彼溫下攪拌過夜。冷卻至室溫後，將溶劑於真 空中移除，令餘留物分界於水及乙醚間，再將水性層以乙 醚萃取兩次。而後將結合之有機層乾燥（硫酸鈉），再將 溶劑於真空中移除以得黑色油狀物。將此油狀物於髙度真 空下，於約9 5 °C下蒸餾，即得清澈油狀之檫題化合物（ 2.75克，81.6%產率）。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）—296 486469 A7 B7Ordered by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, it will be printed under argon (triphenylphosphine) palladium. (70 mg, 0.6 mmol) was added to a solution of degassed 2-bromopyridine (1.9 ml, 20 mmol) in ethylene glycol dimethyl ether (60 ml). After stirring for 10 minutes, 2-tolyl boric acid (2.9 g, 22 mmol) was added, followed by sodium bicarbonate (5.04 g, 60 ml of 60 ml of water), and then The mixture was heated to reflux (about 85 ° C) and stirred at that temperature overnight. After cooling to room temperature, the solvent was removed in the air, the residue was delimited between water and ether, and the aqueous layer was extracted twice with ether. The combined organic layers were then dried (sodium sulfate) and the solvent was removed in vacuo to obtain a black oil. The oily substance was distilled under a vacuum of 髙 ° C and at about 95 ° C to obtain the title compound (2.75 g, 81.6% yield) as a clear oil. This paper size applies to China National Standard (CNS) A4 (210X297 mm) —296 486469 A7 B7

五、發明説明（294 ) 1 '· B · COOHV. Description of the invention (294) 1 '· B · COOH

將第A部化合物（850毫克，5 . 0毫莫耳）及過 錳酸鉀（1 · 9克，12 · 0毫莫耳）之水（2 5毫升） 溶液加熱至迴流（約10 0°C)，再於彼溫下攪拌1小時 。而後將熱反應混合物過濾，再將濾液蒸發至乾。令固狀 餘留物溶於水（5毫升）中，再以乙酸酸化成pH4 - 5 。而後將所得沈澱物藉過濾法離析並以水潤洗以得白色固 狀物（8 0 0毫克），將其由熱乙醇（1 2毫升）中再結 晶後，即得白色固狀之標題化合物（4 5 3毫克， 4 5 · 3 % 產率）。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 c(i) ·A solution of Part A compound (850 mg, 5.0 mmol) and potassium permanganate (1.9 g, 12.0 mmol) in water (25 ml) was heated to reflux (about 100 °). C), and stirred at that temperature for 1 hour. The hot reaction mixture was then filtered and the filtrate was evaporated to dryness. The solid residue was dissolved in water (5 ml) and acidified to pH 4-5 with acetic acid. The precipitate was isolated by filtration and washed with water to obtain a white solid (800 mg). After recrystallization from hot ethanol (12 ml), the title compound was obtained as a white solid. (4 5 3 mg, 4 5 · 3% yield). (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs c (i) ·

於0°C下，將正丁基鋰（2 · 5莫耳濃度，2 1 1毫 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 297 - 486469 A7 B7 五、發明説明（295 ) 升，5 Ί3 0毫莫耳）之四氫呋喃溶液逐滴加至9 一芴羧酸 (5 0克，240毫莫耳）之四氫呋喃（1 2 0 0毫升） 溶液中。再將黃色反應於〇°C下攪拌1小時，而後將1， 4 一二溴丁烷（31 · 3毫升，260毫莫耳）於30分 鐘期間加入。再將反應於0°C下攪拌3 0分鐘，繼而將反 應加溫至室溫3 0小時，再將反應以水萃取（3 X 7 5 0 毫升）。而後將結合之水性層以乙醚（8 0 0毫升）萃取 。繼而將水性層以氫氯酸溶液（1當量濃度，5 0 0毫升 )使成酸性，再以二氯甲烷萃取（3x750毫升）。而 後將結合之有機層於硫酸鎂上乾燥。蒸發後即得白色固狀 之標題化合物（71克，85%)。 c(2) . 1At 0 ° C, n-butyllithium (2.5 mole concentration, 2 1 1 milliliter paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 297-486469 A7 B7 V. Description of the invention (295) liters of a solution of 5 to 30 millimoles in tetrahydrofuran was added dropwise to a solution of 9 monoammonium carboxylic acid (50 grams, 240 millimoles) in a solution of tetrahydrofuran (120 milliliters). The yellow reaction was stirred for an additional hour at 0 ° C, and then 1,4-dibromobutane (31.3 ml, 260 mmol) was added over a period of 30 minutes. The reaction was stirred at 0 ° C for 30 minutes, and then the reaction was warmed to room temperature for 30 hours. The reaction was then extracted with water (3 x 750 ml). The combined aqueous layer was then extracted with ether (800 ml). The aqueous layer was then made acidic with a hydrochloric acid solution (1 equivalent concentration, 500 ml), and extracted with dichloromethane (3 x 750 ml). The combined organic layer was then dried over magnesium sulfate. Evaporation gave the title compound (71 g, 85%) as a white solid. c (2). 1

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 於氬下，於0°C下，將草醯氯（104毫升，2 . 0 莫耳濃度之二氯甲烷，2 0 8毫莫耳）逐滴加至第C (1 )部酸（60克，173毫莫耳）及二甲基甲醯胺（ 1 0 0微升）之二氯甲院（6 0 0毫升）溶液中，再將反 應於0°C下攪拌1 0分鐘，而後加溫至室溫，再攪拌 1 . 5小時。繼而將反應於真空中濃縮以得黃色油狀之粗 製醯基氯β再於0°C下，於氬下，將三乙胺（7 3毫升， 521毫莫耳）加至2，2，2 —三氟乙胺氫氯酸鹽（ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）-298 - 486469 A 7 _ B7五、發明説明（296 ) 25 克，191毫莫耳）之二氯甲烷（500毫升） 懸浮液中，繼而將粗製醯基氯之二氯甲烷溶液（1 5毫升 )逐滴加入，再將反應於0°C下攪拌1小時，以二氯甲烷 (500毫升）稀釋，及以水（2x300毫升），1當 量濃度氫氯酸（2x300毫升），飽和碳酸氫鈉（2x 300毫升），及鹽水（2x 300毫升）清洗，而後於 硫酸鎂上乾燥。蒸發後可得8 0克油狀物，再藉於矽膠（ 2 · 5公斤）上進行急驟色層分離法予以純化。將粗製產 物裝填於二氯甲烷及己烷之混合液中，並以10%乙酸乙 酯/己烷（4升）至1 5%乙酸乙酯/己烷（2升）至2 %乙酸乙酯/己烷（4升）進行梯度洗提。再將純溶離份 收集並予蒸發，即得白色固狀之標題化合物（52 . 5克 ，71%)(熔點 88 - 92 °C)。 (請先閲讀背面之注意事項再填寫本寊)(Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed it under argon, and at 0 ° C, chloramphenicol (104 ml, 2.0 moles of dichloride) Methane, 2.0 mmol) was added dropwise to the C (1) acid (60 g, 173 mmol) and dimethylformamide (100 μl) in dichloromethane (6 (0 ml) solution, the reaction was stirred at 0 ° C for 10 minutes, and then warmed to room temperature, and then stirred for 1.5 hours. The reaction was then concentrated in vacuo to give the crude fluorenyl chloride β as a yellow oil, and triethylamine (73 ml, 521 mmol) was added to 2, 2, 2 at 0 ° C under argon. —Trifluoroethylamine hydrochloride (This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) -298-486469 A 7 _ B7 V. Description of the invention (296) 25 grams, 191 millimoles) To a suspension of dichloromethane (500 ml), a crude dichloromethane solution (15 ml) of dichloromethane was added dropwise, and the reaction was stirred at 0 ° C for 1 hour. Dichloromethane (500 It was diluted with water and washed with water (2x300ml), 1N hydrochloric acid (2x300ml), saturated sodium bicarbonate (2x300ml), and brine (2x300ml), and dried over magnesium sulfate. 80 g of oil was obtained after evaporation, and then purified by flash chromatography on silica gel (2.5 kg). The crude product was filled in a mixture of dichloromethane and hexane, and 10% ethyl acetate / hexane (4 liters) to 15% ethyl acetate / hexane (2 liters) to 2% ethyl acetate / Hexane (4 L) for gradient elution. The pure soluble fractions were collected and evaporated to give the title compound (52.5 g, 71%) as a white solid (melting point: 88-92 ° C). (Please read the notes on the back before filling in this card)

經濟部中央標準局員工消費合作社印製 於〇°C下，將二碳酸二特丁酯（25 · 2克，115 毫莫耳）之二氯甲烷（5 0毫升）溶液逐滴（約3 0分鐘 )加至4 一胺基笮基哌啶（20克，105毫莫耳）之二 氯甲烷（2 0 0毫升）溶液中。再將反應於室溫下攪拌2 小時，而後蒸發以得灰白色固狀物。繼而將產物以乙醚碾 磨（2x20毫升）以得白色固狀物（26 · 5克，90 % )，令產物溶於乙醇（200毫升）中。再於室溫下， 將冰醋酸（10毫升，177毫莫耳）及10%鈀/活性 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）— 486469 A7 __ B7 _ 五、發明説明（297 ) 碳（2” 6克）加至所得溶液中。令其於帕爾儀器（初始 壓爲4 0 p s i )上保持氫化作用1 9小時，再令反應通 過寅氏鹽中過濾，而後將濾液濃縮至乾，繼而令餘留物溶 於氯仿（5 0 0毫升）中，再以1當量濃度已以氯化鈉飽 和之氫氧化鉀（3 X 1 0 0毫升）清洗。而後將水性層結 合並以氯仿萃取（3x80毫升），繼而將結合之有機相 於硫酸鈉上乾燥，並予蒸發，即得白色固狀之標題化合物 (16 克，90%)(熔點 15 7 —1 5 9 X )。 c⑷· (請先閲讀背面之注意事項再填寫本頁)The Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs printed a solution of di-tert-butyl dicarbonate (25.2 g, 115 mmol) in dichloromethane (50 ml) dropwise (about 30) at 0 ° C. Minutes) was added to a solution of 4-aminoaminopiperidine (20 g, 105 mmol) in dichloromethane (200 ml). The reaction was stirred at room temperature for 2 hours and then evaporated to give an off-white solid. The product was then triturated with ether (2 x 20 ml) to give a white solid (26.5 g, 90%), and the product was dissolved in ethanol (200 ml). Then at room temperature, apply glacial acetic acid (10 ml, 177 mmol) and 10% palladium / reactive paper to the Chinese National Standard (CNS) A4 specification (210X297 mm) — 486469 A7 __ B7 _ V. Invention Note (297) carbon (2 "6 g) was added to the resulting solution. Let it remain hydrogenated on a Parr instrument (initial pressure 40 psi) for 19 hours, then filter the reaction through Yin's salt and then The filtrate was concentrated to dryness, and the residue was dissolved in chloroform (500 ml), and washed with 1 equivalent of potassium hydroxide (3 x 100 ml) saturated with sodium chloride. The layers were combined and extracted with chloroform (3x80 ml). The combined organic phases were dried over sodium sulfate and evaporated to give the title compound (16 g, 90%) as a white solid (melting point 15 7-1 5 9 X). C⑷ · (Please read the notes on the back before filling in this page)

將第C (2)部化合物（2 9 · 5克，69 · 2毫莫 耳），第C ( 3 )部化合物（1 4 · 5克，7 2 · 7毫莫 經濟部中央標準局員工消費合作社印製 耳）及無水碳酸鉀（11 · 5克，83 · 0毫莫耳）之二 甲基甲醯胺（1 0 0毫升）混合液於5 0°C下攪拌4 8小 時，濃縮至乾，再置於二氯甲烷（500毫升）中，而後 將溶液以飽和碳酸氫鈉（3 X 8 0毫升）及鹽水（2 X 8 0毫升）清洗，繼而於硫酸鎂上乾燥，蒸發後可得黃色 油狀物，再將其藉於矽膠上（6 0 0克）進行急驟色層分 離法，裝填於二氯甲烷中，並以2%甲醇/二氯甲烷（3 升）至3%甲醇/二氯甲烷（4升）進行梯度洗提而予以 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）—3〇〇 - 486469 A7 B7 五、發明説明（298 ) 純化。再將純溶離份結合並予蒸發，即得白色泡沫膠狀之 標題化合物（30克，86%)。 C(5).Consumption of the compound of Part C (2) (29.5 g, 69 · 2 mmol), the compound of Part C (3) (14 · 5 g, 7 2 · 7 mmol) Co-printed ear) and dimethylformamide (100 ml) in anhydrous potassium carbonate (11.5 g, 83.0 mmol) were stirred at 50 ° C for 4 8 hours and concentrated to Dried, then placed in dichloromethane (500 ml), then the solution was washed with saturated sodium bicarbonate (3 x 80 ml) and brine (2 x 80 ml), and then dried over magnesium sulfate. A yellow oil was obtained, which was then subjected to flash chromatography on silica gel (600 g), filled in dichloromethane, and 2% methanol / dichloromethane (3 liters) to 3% methanol. / Dichloromethane (4 liters) was subjected to a gradient elution and the paper size was applied to the Chinese National Standard (CNS) A4 specification (210X297 mm)-300-486469 A7 B7 5. Purification of the invention (298). The pure soluble fractions were combined and evaporated to give the title compound (30 g, 86%) as a white foam. C (5).

將4當量濃度氫氯酸之二噁烷液（1 2 1毫升， 483毫莫耳）加至第C (4)部化合物（30 ·5克， 60 · 4毫莫耳）之二噁烷（120毫升）溶液中。再將 反應於室溫下攪拌4小時，而後於真空中濃縮，即得含餘 留量二噁烷之白色泡沬固狀之標題化合物（30克）。 D · 9 -〔4 一〔4 一〔（2 - Β比Β定基苯醯）胺基〕一 1 一哌啶基〕一 丁基〕一Ν —（2，2，2 —三氟乙基） 二9 Η -芴一 9 —甲醯胺，二氣氯酸鹽__ 經濟部中央標準局員工消費合作社印製 將草醯氯（110微升，1 · 3毫莫耳）加至第Β部 酸（145毫克，0 · 7毫莫耳）之二氯甲烷（2毫升） 溶液中，繼而將數滴二甲基甲醯胺加入。’反應乃強烈起泡 ’轉黃，再於氬下，於室溫下攪拌2小時，而後將溶劑於 真空中，於低於2 5 °C之溫度下蒸發，再令餘留物溶於二 氯甲烷（5毫升）中，繼而於一 5 °C下，將此溶液逐滴加 至第C部二胺（30 0毫克，0 · 6毫莫耳）及三乙胺（ 301 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐） 486469 經濟部中央標準局員工消費合作社印製 A7 _-一_B7_ 五、發明説明（299 ). 400微升，2 · 9毫莫耳）之二氯甲烷（5毫升）溶液 中，再將反應於熔化之冰浴中攪拌過夜。而後將反應混合 物以二氯甲烷稀釋及以水清洗一次。繼而將有機層以i當 量濃度氫氯酸萃取兩次。再使用1當量濃度氫氧化鈉使結 合之酸萃取物成鹼性，而後以乙酸乙酯萃取兩次。再將結 合之乙酸乙酯層乾燥（硫酸鈉），並將溶劑於真空中移除 以得棕色油狀物，繼而將其藉急驟柱色層分離法（氧化矽 ，9 0克）並以5 %甲醇：0 · 5 %氫氧化銨：二氯甲烷 洗提而予以純化以得清澈油狀物（1 7 0毫克，4 6 . 8 %產率）。令1 6 0毫克此油狀物溶於甲醇（2毫升）中 ，再將1 · 1當量濃度醚性氫氯酸（8 0 0微升）加入， 而後將溶劑於真空中移除，即得淡黃色固狀之標題化合物 (1 7 3毫克）。 熔點1 46 — 50 °C (分解） MS (ESI ，+ 離子）m/z 6 2 7 ( Μ + Η ) 分析·Χ37Η37ΝΡ3Ν4〇2· 2HCj? + 2H2〇之計算 值： C，6 0 · 4 1 ; Η，5 · 8 9 ; N，7 · 6 2 實測值：C，6 〇 · 3 8 ; Η，5 · 8 6 ; Ν，7 · 5 0 ο 下列化合物係使用上文所述之步驟製得。 實例1 1 a * 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ - (請先閱讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（3〇〇 )Add 4 equivalents of hydrochloric acid in dioxane (121 ml, 483 mmol) to Part C (4) compound (30 · 5 g, 60 · 4 mmol) dioxane ( 120 ml) solution. The reaction was stirred at room temperature for 4 hours, and then concentrated in vacuo to obtain the title compound (30 g) as a white foamy solid containing the remaining amount of dioxane. D · 9-[4-[4-[(2-Β than B phenylphenylhydrazone) amine]-1 -piperidinyl] -butyl] -N — (2,2,2-trifluoroethyl) 2 9 Η-芴 1 9-formamidine, dichlorochlorate __ Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Add chlorchloride (110 μl, 1.3 mmol) to Part B. To a solution of the acid (145 mg, 0.7 mmol) in dichloromethane (2 ml) was added a few drops of dimethylformamide. The 'reaction is intense foaming' turned yellow, and then stirred under argon at room temperature for 2 hours, then the solvent was evaporated in vacuo at a temperature below 25 ° C, and the residue was dissolved in two In methyl chloride (5 ml), and then at -5 ° C, add this solution dropwise to Part C diamine (300 mg, 0.6 mmol) and triethylamine (301 (please read first Note on the back, please fill in this page again) This paper size is applicable to Chinese National Standard (CNS) A4 specification (21.0X297mm) 486469 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _- 一 _B7_ V. Description of the invention (299 ). 400 microliters of 2.9 millimoles) in dichloromethane (5 ml). Stir the reaction in a melting ice bath overnight. The reaction mixture was then diluted with dichloromethane and washed once with water. The organic layer was then extracted twice with hydrochloric acid of i equivalent concentration. The combined acid extract was made alkaline with 1 equivalent of sodium hydroxide and then extracted twice with ethyl acetate. The combined ethyl acetate layer was dried (sodium sulfate), and the solvent was removed in vacuo to obtain a brown oil. Then, it was separated by flash column chromatography (silica, 90 g), % Methanol: 0.5% ammonium hydroxide: dichloromethane was eluted and purified to obtain a clear oil (170 mg, 46.8% yield). Dissolve 160 mg of this oil in methanol (2 ml), add 1.1 equivalents of etheric hydrochloric acid (800 microliters), and then remove the solvent in vacuo to obtain The title compound as a pale yellow solid (173 mg). Melting point 1 46 — 50 ° C (decomposition) MS (ESI, + ions) m / z 6 2 7 (Μ + Η) analysis · Calculated value of χ37Η37NP3N4〇2 · 2HCj? + 2H2〇: C, 6 0 · 4 1 Η, 5 · 8 9; N, 7 · 6 2 found: C, 6 〇 3 8; Η, 5 · 8 6; Ν, 7 · 5 0 ο The following compounds were prepared using the procedures described above. Got. Example 1 1 a * This paper size is in accordance with China National Standard (CNS) A4 (210X297 mm) _-(Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (300)

4 2 V—- /IVI I 9 N 4 2 基噸 啶噻 哌 |I Η 1 ObI I 基基 胺乙 醯氟 苯三 基 醯 甲I 94 2 V—- / IVI I 9 N 4 2 yl tonidine piperazine | I Η 1 ObI I based amine ethyl fluorinated benzenetriyl fluorene methyl I 9

Η+ Μ /IV 2 8 5 ζ / oc m 0 \JX 5 子 1 離 鹽 1 + 酸 5 ， 氯 4 S 氨 1 E 單 · C , 點 S 胺熔M 〇 C 2 • Η 析 5 分 7 素 · 元 ο + S 3 F 2 〇 3Ν 4 3Η 2之 3 值 算 計 (請先閲讀背面之注意事項再填寫本頁) + ΠΧ CΗοΗ + Μ / IV 2 8 5 ζ / oc m 0 \ JX 5 ions 1 off-salt 1 + acid 5, chloro 4 S ammonia 1 E mono · C, point S amine melting M OC 2 • 析 analysis 5 points 7 elements · Yuan ο + S 3 F 2 〇3Ν 4 3Η 2/3 calculation (please read the precautions on the back before filling this page) + ΠΧ CΗο

C ο Η 7 Ν 6C ο Η 7 Ν 6

4ο 9 F C 值 測 實 ο 7 Η 6 2 6Νοο4ο 9 F C value measured ο 7 Η 6 2 6Νοο

F 5 1± 經濟部中央標準局員工消費合作社印製F 5 1 ± Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

ο ο 鹽 酸 氯 氫 b 本紙張尺度適用中國國家標準（CNS)A4規格U10X297公釐）_ 3〇3 一 486469 A7 B7 五、發明説明（301)ο ο Hydrochloric acid Hydrochloric acid b The paper size is applicable to the Chinese National Standard (CNS) A4 specification U10X297 mm) _3〇3 486469 A7 B7 V. Description of the invention (301)

9 一〔4 一〔4 一〔 （2 -苯氧基苯醯）胺基〕一 1 一哌 啶基〕丁基—N -（2，2，2 —三氟乙基）—9H -噻 噸一9一甲醯胺，單氫氯酸鹽 熔點.204 — 208°C “3(£3，+離子）111/2 578 (M + H) 元素分析· C38H38〇3S F3N3+ 1 HC芡+ 0 · 5 Η 2 0之計算值： C，6 3 · 4 6 ; Η，5 · 6 1 ; Ν，5 . 8 4 ;S，4 · 4 6 實測值：C，63.45;H，5.51;N，5.72 ;S ， 4 . 1 5 ° 實例1 3 $9- [4- [4-[(2-phenoxyphenylhydrazone) amino] -1 1-piperidinyl] butyl-N- (2,2,2-trifluoroethyl) -9H-thioxanthene Monomethylamine, melting point of monohydrochloride. 204 — 208 ° C "3 (£ 3, + ion) 111/2 578 (M + H) Elemental analysis · C38H38〇3S F3N3 + 1 HC 芡 + 0 · Calculated values for 5 Η 2 0: C, 6 3 · 4 6; Η, 5 · 6 1; Ν, 5. 8 4; S, 4 · 4 6 Found: C, 63.45; H, 5.51; N, 5.72 ; S, 4.1. 5 ° Example 1 3 $

經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 9 —〔4 —〔4 一〔（〔1 ，1 一聯苯基〕—4 —基鑛基 )胺基〕一 1 一哌啶基〕—3 ，3 —二甲基丁基〕一 N-(2 ，2 ，2 —三氟乙基）一 9H —芴一 9 一甲醯胺，單 氫氯酸鹽 本紙張尺度適用中國國家標準（0奶）八4規格（2丨0\297公釐）__3〇4一 — 486469 A7 B7 五、發明説明（302 )Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 9 — [4 — [4 1 [([1,1 Biphenyl] -4—Base-based) amine Group] -1,1-piperidinyl] -3,3-dimethylbutyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-methaneamine, monohydrochloric acid The size of the salt paper is applicable to the Chinese national standard (0 milk) 8 4 specifications (2 丨 0 \ 297 mm) __304. 1 — 486469 A7 B7 5. Description of the invention (302)

熔點· 9 5 — 1 Ο 1 °C MS (電噴霧，一離子）m/z 654 (M + H)。 實例1 4 $Melting point · 9 5 — 1 Ο 1 ° C MS (electrospray, single ion) m / z 654 (M + H). Example 1 4 $

二氫氯酸鹽 9_〔4 一〔4 一〔〔（3 -苯基-2 -吡啶基）羰基〕 胺基〕一 1—呢n定基〕丁基〕一 N— (2，2，2 —三氟 乙基）一9H—芴一9一甲醯胺，二氫氯酸鹽 MS (ESI ，+ 離子）m/z 6 2 7 ( Μ + Η ) + ； (ESI ，一離子）m/z 625 (M-H)- (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 實例1 5 'Dihydrochloride 9_ [4-[4-[[(3-phenyl-2-pyridyl) carbonyl] amino] -1-n-n-yl] butyl] -N- (2,2,2- Trifluoroethyl) -9H-fluorene-9-methylamidine, dihydrochloride MS (ESI, + ion) m / z 6 2 7 (Μ + Η) +; (ESI, single ion) m / z 625 (MH)-(Please read the notes on the back before filling out this page) Printed by the Consumers 'Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 1 5'

N —〔 1 一〔 4 —〔 9 一〔 〔 （2 ，2 ，2 —三氟乙基） 胺基〕羰基〕一 9 Η -芴一 9 一基〕丁一 1 一基〕哌啶— 1 一基〕—2 —〔Ν — (2，2，2 -三氟乙基）胺基〕 本紙張尺度適用中國國家標準（CNS ) Α4規格（21.0X297公釐）_ 305 - 486469 A7 B7 五、發明説明（3〇3 ) 吡啶一3-甲醯胺，氫氯酸鹽 1^13 (£51，+離子）111/2 648 (M + H)； (ESI ，_離子）m/z 646 (Μ—Η)。 實例N — [1 a [4 — [9 a [[(2,2,2-trifluoroethyl) amino] carbonyl]] 9 9 9-Η 9 9 yl] butan 1 1 yl] piperidine — 1 One base] —2— [N — (2,2,2-trifluoroethyl) amine] This paper size applies to China National Standard (CNS) A4 specification (21.0X297 mm) _ 305-486469 A7 B7 V. Description of the invention (3〇3) pyridin-3-formamidine, hydrochloride 1 ^ 13 (£ 51, + ion) 111/2 648 (M + H); (ESI, _ ion) m / z 646 ( M—Η). Examples

Ν (請先閲讀背面之注意事項再填寫本頁) 含0 . 1莫耳乙醚 Ν —〔 1-〔4 —〔 9 一〔 〔 （2，2 ，2-三氟乙基） 胺基〕碳基〕—9Η -荀一 9 一基〕丁一 1—基〕哌陡一 4 一基〕一 2 -苯基吡啶一 3 -甲醯胺，氫氯酸鹽 MS (ESI — ΝΗ3，+ 離子）627 (Μ + Η)。 實例1 7 $ 經濟部中央標隼局員工消費合作社印製Ν (Please read the notes on the back before filling this page) Contains 0.1 mol ether N— [1- [4 — [9 a [[(2,2,2-trifluoroethyl) amino] carbon] Base] -9Η-fluorene-9-yl] butan-1-yl] piperazine-4-yl] -2-phenylpyridine-3-methylamine, hydrochloride MS (ESI — ΝΗ3, + ion) 627 (Μ + Η). Example 1 7 $ Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）^ 3〇6 一 486469 A7 B7 五、發明説明（304 ) 9一〔4 —〔4 —〔 （〔1 ，1 一聯苯基〕一 4一 基羰基 )胺基〕一 1—呢B定基〕一 3 -經基丁基〕一 N -（2， 2 ，2 —三氟乙基）一 9H —芴一 9 一甲醯胺，單氫氯酸 鹽This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 306-6486469 A7 B7 V. Description of the invention (304) 9 一 [4 — [4 — [(1, 1 biphenyl ] 4- 4-carbonylcarbonyl) amine] 1-n-B-radical] 3- 3-butylidene]-N-(2, 2, 2, 3-trifluoroethyl)-9H-fluorene-9-methylamine , Monohydrochloride

熔點· 1 6 3 — 1 6 5 °C MS (電噴霧，+ 離子）m/z 6 4 2 ( M + Η )。 (請先閲讀背面之注意事項再填寫本頁) 賨例1 8 $Melting point 1 6 3 — 1 6 5 ° C MS (electrospray, + ion) m / z 6 4 2 (M + Η). (Please read the notes on the back before filling this page) 賨 例 1 8 $

經濟部中央標準局員工消費合作社印製 9 一〔4 一〔4 一〔〔 （4 —氟基一3 — 甲苯基）一 2 — 吡啶基）羰基〕胺基〕一 1 一哌啶基〕丁基〕——Ν -（ 2 ，2 ，2 —三氟乙基）一 9 Η —芴一9 一甲醯胺，二氫氯 酸鹽 MS (ESI.，+ 離子）m/z 659 (M + H)+; (ESI ，—離子）m/z 657 (Μ - Η)-元素分析· C38H38F4N402+2HC5 + 1. 5Η2〇 + 0 · 2Ε t20 + 〇 · 2二噁烷之計算值： C，6 Ο · 1 2 ; Η，5 · 9 4 ; N，7 · 0 8 ;F，9:61;Cj?，8.96 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 307 - — 486469 A7 B7 五、發明説明（ 305 ) 實測值：C，60.17;H，5.89;N，7.24 ;F，l〇.48;Cj?，8.91° 實例1 9 $Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 9-[4-[4-[[(4-fluorofluoro-3-tolyl)-2-pyridyl) carbonyl] amine]-1-piperidinyl] Ding Group] —— N-(2,2,2-trifluoroethyl)-9 Η-芴-9-methylamine, dihydrochloride MS (ESI., + Ion) m / z 659 (M + H) +; (ESI,-ion) m / z 657 (Μ-Η) -Elemental analysis · C38H38F4N402 + 2HC5 + 1. 5Η2〇 + 0 · 2E t20 + 〇 2 Dioxane Calculated value: C, 6 〇 · 1 2; Η, 5 · 9 4; N, 7 · 0 8; F, 9:61; Cj ?, 8.96 This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 307-— 486469 A7 B7 V. Description of the invention (305) Measured value: C, 60.17; H, 5.89; N, 7.24; F, 10.48; Cj ?, 8.91 ° Example 1 9 $

二氫氯酸鹽 (請先閲讀背面之注意事項再填寫本頁) 9 一〔4 一〔4 一〔〔〔3 -（2 —噻嗯基）一 2 —吡啶 基〕鐵基〕胺基〕一 1 一喊B定基〕丁基〕一 N -（ 2，2 ，2 —三氟乙基）—9 H —荀一 9 —甲醯胺，二氫氯酸鹽、 MS (ESI ，+ 離子）m/z 6 3 3 ( Μ + Η ) + ； (ESI ，-離子）m/z 631 (Μ — H)- 實例2 Ο $Dihydrochloride (Please read the precautions on the back before filling out this page) 9-[4-[4-[[[3--(2-thienyl)-2-pyridyl] iron] amine] -1-B-Amino group-Butyl]-N-(2, 2, 2-trifluoroethyl)-9 H-fluorene-9-formamidine, dihydrochloride, MS (ESI, + ion) m / z 6 3 3 (Μ + Η) +; (ESI, -ion) m / z 631 (Μ — H)-Example 2 Ο $

經濟部中央標準局員工消費合作社印製 Ν —（2 ，2 ，2 —三氟乙基）一 9一〔4 一〔4-〔〔 〔2 —〔 （2，2，2 —三氣乙基）硫基〕—3—11比陡基 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）-3〇8 一 486469 A7 B7 五、發明説明（306 ) 〕羰基〕胺基〕一 1 一哌啶基〕丁基〕一 9H -芴一 9 一 甲醯胺，二氫氯酸鹽 MS (ES I— NH3，+ 離子）665 (M + H)； 6 6 3 〔 Μ — Η〕 〇 (請先閲讀背面之注意事項再填寫本頁) 9 —〔4 一〔4 —〔 〔2 —（2，2 ，2 —三氟乙氧基） 苯醯〕胺基〕—1 一哌Β定基〕丁基〕一 Ν — (2，2，2 —三氟乙基）一 9 Η —芴一 9 一甲醯胺，單氫氯酸鹽 MS (電噴霧，+離子）m/z 648 (M+H)。 經濟部中央標準局員工消費合作社印製 實例2 2Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs N— (2,2,2-trifluoroethyl) —9— [4— [4-[[[2 — [(2,2,2-trifluoroethyl) ） Sulfur group] —3-11 than steeper basic paper size applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) -308-486469 A7 B7 5. Description of the invention (306) carbonyl group] amine group] -1 Monopiperidinyl] butyl] -9H-fluorene-9monomethylamine, dihydrochloride MS (ES I—NH3, + ion) 665 (M + H); 6 6 3 [M — Η] 〇 (Please read the precautions on the back before filling out this page) 9 — [4 a [4 — [[2 — (2, 2, 2, 2-trifluoroethoxy) phenylhydrazine] amine]] 1-piperidine 〕 Butyl] -N — (2,2,2-trifluoroethyl) — 9 Η — 芴 — 9 —methylamine, monohydrochloride MS (electrospray, + ion) m / z 648 (M + H). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Example 2 2

9 -〔 4 一〔 4 一〔 〔 （ 3 -環己基一 2 -吡啶基）羰基 〕胺基〕一 1 一哌啶基〕丁基〕一 N — ( 2 ，2 ，2 —三 實例2 1 $9-[4-[4-[[((3-Cyclohexyl-2 -pyridyl) carbonyl) amino] -1 -piperidinyl] butyl) -N-(2, 2, 2, 2-three examples 2 1 $

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 3〇9 一 486469 A7 B7 五、發明説明（3〇7 ) 氟乙基） Η -芴一 9 一甲醯胺，二氫氯酸鹽 ΜΗ ( -3 Μ 3 ( CO r—I 3 z 6 / m z } \ 子 m 離 } +子 1三 ’ 離 I I S ， E I ( S s E M ( + \1/ Η c Ε • 5 析2 分 . 素 ο 元 + 2 4 Η 7 3 〇 2This paper size applies to China National Standard (CNS) A4 (210X297 mm)-3009-486469 A7 B7 5. Description of the invention (307) fluoroethyl) Η-芴-9-methylamine, dihydrogen Chlorate ΜΗ (-3 Μ 3 (CO r—I 3 z 6 / mz} \ 子 m out) + 子 1 三 'from IIS, EI (S s EM (+ \ 1 / Η c Ε • 5 analysis 2 Fen. Element ο Yuan + 2 4 Η 7 3 〇 2

2 40值 Ν算 3 F 計 之 〇 2 Η 5 1± + nx c Η 2 值 測 實 Ν Ν 。 •, 00 ; 0〇 0 4 8 8 6 · 9 · • 9 · 9 6 ， 6 ， ， ηχ ， ΟΑ H c H C 9 8 9 5 6 5 8 2 0 7 0 7 6 ， 6 , ， F , F ·, ·, 5 4 7 r-H 5 7 (請先閲讀背面之注意事項再填寫本頁)2 40 value Ν is calculated as 3 F 〇 2 Η 5 1 ± + nx c Η 2 value measured Ν Ν. •, 00; 0〇0 4 8 8 6 · 9 · • 9 · 9 6, 6,, ηχ, 〇Α H c HC 9 8 9 5 6 5 8 2 0 7 0 7 6, 6,, F, F · , ·, 5 4 7 rH 5 7 (Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製 基基 。 胺乙 } 3 氟Η 醯三 + 苯 IΜ ) 2 ( rk 基， 5 〇人 咐2 鹽 3 ΝΗ 嗎，酸 6 1 2 氯 4 C 氫 Ζ C I 單 \lN，m 2 | 胺 } f DK子 C 基甲離 I 丁 I + 4 ] 9 » t 基 一霧 I 啶芴噴 4 哌 I 電 c - Η ( | 一—19 S 9 1 | Μ 4 2 例 實 本紙張尺度適用中國國家標準（CNS)A4規格（210X297公釐）—31〇 _ 486469 A7 B7 五、發明説明（3〇8 )Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Amine ethyl} 3 Fluorofluorene hydrazine + benzene IM) 2 (rk group, 50 hrs 2 salt 3 ΝΗ, acid 6 1 2 chlorine 4 C hydrogen Z CI mono \ lN, m 2 | amine} f DK daughter C Chitosan I butyl I + 4] 9 »t JI Yiwu I 芴 芴 spray 4 pi I c c-Η (| -1919 S 9 1 | Μ 4 2 examples The paper size applies to the Chinese National Standard (CNS) A4 specifications (210X297 mm)-31〇_486469 A7 B7 V. Description of the invention (308)

9 一〔4 一〔4 —〔（4 —氯基一 3 - D比b定基）碳基〕胺 基〕一 1—哌啶基〕丁基〕一 N — (2，2，2 —三氟乙 基）一 9H —芴一 9 一甲醯胺，二氫氯酸鹽9 [[4] [4-[(4-Chloro-1,3-D than b-Amino) carbon-] amino] -1-piperidinyl] butyl] -N- (2,2,2-trifluoro Ethyl) -9H-fluorene-9-methaneamine, dihydrochloride

熔點· 1 6 5 - 7 3 °C MS (ESI ，+ 離子）m/z 5 8 5 ( Μ + Η )。 (請先閱讀背面之注意事項再填寫本頁) 實例2 5 &gt;Melting point 1 6 5-7 3 ° C MS (ESI, + ion) m / z 5 8 5 (Μ + Η). (Please read the notes on the back before filling this page) Example 2 5 &gt;

經濟部中央標準局員工消費合作社印製 9 一〔4 一〔4 一〔 〔2 — (4 — 甲基一 1 一 Β 比瞭基）苯 醯〕胺基〕一 1 一哌啶基〕丁基〕一 N — (2，2，2 — 三氟乙基）—9 Η —荀一 9 一甲醯胺，二氫氯酸鹽 MS (鼇噴霧，+ 離子）m/z 648 (M + H)。 實例2 6 $ 本紙張尺度適用中國國家標準（ CNS)A4規格（ 210X297公釐）_ 311 一Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 9-[4-[4-[[2 — (4-methyl-1 1-B compared with phenyl) phenyl]] amino]-1-piperidinyl] butyl 〕 -N — (2,2,2 —trifluoroethyl) —9 Η — 荀 -9 9 Methylamine, dihydrochloride MS (Ao spray, + ion) m / z 648 (M + H) . Example 2 6 $ This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 311 一

486469 A7 B7 五、發明説明（3〇9 ) h486469 A7 B7 V. Description of the invention (309) h

反式一 9 一〔4 一〔4 一〔〔 （2 - 苯基一 3 -環己—1 一基）羰基〕胺基〕一 1 一哌啶基〕丁基〕一 N -（ 2， 2 ，2 —三氟乙基）一 9H —芴一 9 一甲醯胺，單氫氯酸 鹽Trans one 9 one [4 one [4 one [[(2-phenyl-3-cyclohexyl-1-yl) carbonyl] amino] -1 1-piperidinyl] butyl] -N-(2, 2 , 2-trifluoroethyl) -9H-fluorene-9-methylamine, monohydrochloride

熔點.1 6 0 — 1 6 3 °C MS (電噴霧，+ 離子）m/ z 6 3 0 ( M + Η )。 實例2 7 # (請先閱讀背面之注意事項再填寫本頁)Melting point. 1 6 0 — 1 6 3 ° C MS (electrospray, + ion) m / z 6 3 0 (M + Η). Example 2 7 # (Please read the precautions on the back before filling this page)

反式一 9 一〔4 一〔4 一〔 〔 （2 —苯基環己基）羰基〕 經濟部中央標準局員工消費合作社印製Trans one 9 one [4 one [4 one [[(2-phenylcyclohexyl) carbonyl]] Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

胺基〕—1 —哌啶基〕丁基〕一 Ν -（ 2，2，2 —三氟 乙基）—9Η —芴一 9 一甲醯胺，單氫氯酸鹽 熔點· 1 5 6 — 1 5 9 °C MS (電噴霧，+離子）m/z 632 (M+H)。 實例2 8 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）一 312 - 486469 A7 B7 五、發明説明（3l〇 )Amine] -1-piperidinyl] butyl] -N- (2,2,2-trifluoroethyl) -9）-芴 -9-Methylamine, melting point of monohydrochloride · 1 5 6 — 1 5 9 ° C MS (electrospray, + ion) m / z 632 (M + H). Example 2 8 This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 312-486469 A7 B7 V. Description of the invention (31)

9 —〔4 —〔4 一〔〔（2 -苯基—3 -噻嗯基）羰基〕 胺基〕一 1 一哌啶基〕丁基〕—N -（2，2，2 -三氟 乙基）一9H—芴一9一甲醯胺，單氫氯酸鹽 MS (ES，+ 離子）m/z 6 3 2 ( M + Η )。 (請先閲讀背面之注意事項再填寫本頁) 實例2 9 $9 — [4 — [4-[[(2-phenyl-3-thienyl) carbonyl] amine]] 1-piperidinyl] butyl] —N-(2,2,2-trifluoroethyl Group)-9H-fluorene-9-methylamidine, monohydrochloride MS (ES, + ion) m / z 6 3 2 (M + Η). (Please read the notes on the back before filling this page) Example 2 9 $

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

9 一〔 4 一〔 4 一〔（ 4 一苯基一 3 -吡啶基）羰基〕胺 基〕一 1—哌啶基〕丁基〕一 Ν —（2 ，2，2 —三氟乙 基）一 9 Η -荀一 9 一甲釀胺，二氫氯酸鹽 熔點· 1 4 4 一 5 0 °C MS (ESI，+ 離子）m/z 6 2 7 ( Μ + Η ) 元素分析· C37H37F3N4〇2+2HCj2 + l · 2Η2〇 之計算值： C，61.6 2;H，5.79;N，7.77 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）一 313 一 486469 A7 B7 五、發明説明（311 ) 實測值：C，6 1 · 6 4 ; Η，5 · 8 0 ; N，7 · 3 2 實例3 09- [4-[4-[(4 -phenyl-3-pyridyl) carbonyl] amino] -1-piperidinyl] butyl] -N — (2,2,2-trifluoroethyl) -9 Η-荀-9 Methylamine, melting point of dihydrochloride · 1 4 4-50 ° C MS (ESI, + ion) m / z 6 2 7 (Μ + Η) elemental analysis · C37H37F3N4〇 Calculated values of 2 + 2HCj2 + l · 2Η2〇: C, 61.6 2; H, 5.79; N, 7.77 This paper size applies to China National Standard (CNS) A4 specification (21.0X297 mm)-313-486469 A7 B7 V. Description of the invention (311) Measured value: C, 6 1 · 6 4; Η, 5 · 8 0; N, 7 · 3 2 Example 3 0

9一〔4 —〔4 一〔〔2 -（1 一哌u定基）苯醯〕胺基〕 一 1 一呢u定基〕丁基〕一 Ν —（2，2，2 -三氟乙基） 一9Η—芴一9一甲醯胺，單氫氯酸鹽 MS (電噴霧，+離子）m/z 633 (M+H)。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 實例3 19- [4 — [4-[[2- (1-Pyridinyl) phenylhydrazine] amino] -1 1-Pyridinyl] butyl] -N— (2,2,2-trifluoroethyl) -9Η- 芴 -9-methylformamide, monohydrochloride MS (electrospray, + ion) m / z 633 (M + H). (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Example 3 1

•TFA MS (ESI，+離子）m/z 618 (M+H)。 實例3 2 $ 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐）一 314 一 一 486469 Α7 Β7 經濟部中央標隼局員工消費合作社印製 五、發明説明（312)• TFA MS (ESI, + ion) m / z 618 (M + H). Example 3 2 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) one 314 one one 486469 Α7 Β7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (312)

實例3 3Example 3 3

CI 9 一〔4 一〔4 一〔〔2 -（2，4 一二氯苯基）苯醯〕 胺基〕一 1—呢卩定基〕丁基〕一 N— (2，2，2 —三氟 乙基）一9H—芴一9一甲醯胺，單氫氯酸鹽 熔點· 1 2 3 — 1 2 8 °C M S (電噴霧，一離子）m / z 6 9 4 ( M + Η )。 實例3 4 $CI 9 mono- [4- mono- [4- mono-[[2--(2,4-dichlorophenyl) phenylhydrazone] amine]] 1-n-pyridinyl] butyl] -N- (2,2,2 -tri Fluoroethyl)-9H—fluorene-9-methylamidine, melting point of monohydrochloride · 1 2 3 — 1 2 8 ° CMS (electrospray, monoion) m / z 6 9 4 (M + Η). Example 3 4 $

本紙張尺度適用中國國家標準（CNS ) Α4規格（2L0X297公釐）一 315 _ (請先閲讀背面之注意事項再填寫本頁) 486469 A7 B7 五、發明説明（313)This paper size applies Chinese National Standard (CNS) Α4 specification (2L0X297 mm) 315 _ (Please read the precautions on the back before filling this page) 486469 A7 B7 V. Description of the invention (313)

9 一〔4 一〔4 —〔〔 （ 6 —苯基一 1 一環己嫌一 1 一基 )鐵基〕胺基〕一 1 一呢B定基〕丁基〕一 N -（2，2， 2—三氟乙基）—9H—芴一9一甲醯胺，單氫氯酸鹽 熔點.1 1 0 — 1 1 4 °C M S (電噴霧，一離子）m / 2 6 3 0 ( M + Η )。 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 9 — C 4 一 C 4 — 〔 ( 2， 5 一二氟苯醯） 胺 基 ]- • 1 一 哌 u定 基 ] 丁 基 ) — Ν 一 (2 ， 2，2 -三氟 乙 基 )一 .9 Η 一 y-f-* 勿 — 9 一 甲 醯 胺 &gt; 單 氫氯 酸 鹽 熔 點 • 8 0 一 8 4 V Μ S ( E S I y + 離 子 )m / ζ 5 8 6 ( Μ + Η) 元 素 分 析 • C 3 2 Η 3 2 F 5N 3 〇 2+ 1 H C j?- Η L . .2 Η 2 〇 之 計 算 值 ； C &gt; 5 9 • 7 1 ； Η ，5 . 5 4 ; Ν 6 · 5 3 寳 測 值 C 5 9 . 6 8 ; Η ，5 · 5 3 ; Ν &gt; 6 . 4 4 實例3 6 實例3 5 #9- [4- [4 -— [[(6-phenyl-1, 1-cyclohexyl-1, 1-yl) iron-based] amine]] 1- 1-B-radical] butyl] -N-(2, 2, 2 —Trifluoroethyl) —9H—fluorene-9-methylamidine, melting point of monohydrochloride. 1 1 0 — 1 1 4 ° CMS (electrospray, monoion) m / 2 6 3 0 (M + Η ). (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 9 — C 4 -C 4 — [(2, 5 difluorophenylhydrazone) amine]-• 1 pipe u-Adenyl] butyl) — Ν mono (2,2,2-trifluoroethyl)-. 9 Η-yf- * Do — 9-methylamine &gt; melting point of monohydrochloride • 8 0-8 4 V Μ S (ESI y + ion) m / ζ 5 8 6 (Μ + Η) Elemental analysis • C 3 2 Η 3 2 F 5N 3 〇2 + 1 HC j?-Η L.. 2 Η 2 〇 Calculation Value; C &gt; 5 9 • 7 1; Η, 5. 5 4; Ν 6 · 5 3 Po measured value C 5 9. 6 8; Η, 5 · 5 3; Ν &gt; 6. 4 4 Example 3 6 Example 3 5 #

本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）-316 - 486469 A7 B7This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) -316-486469 A7 B7

五、發明説明（314 ) 9 一〔4一 一（2，2，2 —三氟甲基）乙氧基〕一 3 —吡啶基〕羰 基〕胺基—1 -吡啶基〕丁基〕一 N — ( 2，2，2 —三 氟乙基）一9H—芴一9一甲醯胺，二氫氯酸鹽 汹3(£3 1，+離子）717 (1^ + ：«); (一離子）7 15(M — H)。 實例3 7 $ (請先閲讀背面之注意事項再填寫本頁)V. Description of the invention (314) 9- [4-one- (2,2,2-trifluoromethyl) ethoxy] -3-pyridyl] carbonyl] amino-1-pyridyl] butyl] -N — (2,2,2-trifluoroethyl)-9H—fluorene-9-methylamine, dihydrochloride 3 (£ 3 1, + ion) 717 (1 ^ +: «); (一Ion) 7 15 (M — H). Example 3 7 $ (Please read the notes on the back before filling this page)

二氫氯酸鹽 經濟部中央標準局員工消費合作社印製 9 一〔 4 —〔 4 —〔〔 （ 4 一苯基一2-妣啶基）羰基〕 胺基〕—1 一哌B定基〕丁基〕一 N -（ 2，2，2 -三氟 乙基）一 9 Η —芴一 9 一甲醯胺，二氫氯酸鹽 M S ( E S I ，+ 離子）m / ζ 6 2 7 ( Μ + Η ) + ； . ·- (E S I ，一離子）m / ζ 6 2 5 ( Μ — Η ) -元寒分析· C37^3Ν 4 0 2+ 2 Η C 又 + .r , / v % - -Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics, Dihydrochloride. 9 [[4 — [4 — [[(4-Phenyl-2-Pyrimidinyl) carbonyl] Amine] -1 Pyridyl] Group] -N-(2,2,2-trifluoroethyl)-9 Η-芴-9-methylamine, dihydrochloride MS (ESI, + ion) m / ζ 6 2 7 (Μ + Η) +;.-(ESI, one ion) m / ζ 6 2 5 (Μ — Η)-Yuan Han analysis · C37 ^ 3N 4 0 2+ 2 Η C again + .r, / v%--

本紙張尺度適用中國國家榡準（CNS -317 - 486469 A7 B7 五、發明説明（315 ) 0 · 44E t2〇 + 3 · 0112〇之計算值： C，59.21;H，6.33;N ;F，7.25;C5，9.02 實測值：C，5 9 · 5 9 ; Η，6 · Ο 1 ; N ;F，7.10;C^，9.17 7 6 7 實例3 8This paper size applies to the Chinese National Standard (CNS -317-486469 A7 B7 V. Explanation of the invention (315) 0 · 44E t2〇 + 3 · 0112〇 Calculated values: C, 59.21; H, 6.33; N; F, 7.25 ; C5, 9.02 found: C, 5 9 · 5 9; Η, 6 · Ο 1; N; F, 7.10; C ^, 9.17 7 6 7 Example 3 8

cf3 ---------衣-- (請先閲讀背面之注意事項再填寫本頁) 9 —〔4 一〔4 —〔 〔2，6 —雙（三氟甲基）苯醯〕胺 基〕一 1 一哌啶基〕丁基〕一 N— (2，2，2 -三氟乙 基）一 9 Η -芴一 9 一甲醯胺，單氫氯酸鹽cf3 --------- 衣-(Please read the precautions on the back before filling out this page) 9 — [4 a [4 — [[2,6 —bis (trifluoromethyl) phenylhydrazone]] Amine]-1-piperidinyl] butyl] -N- (2,2,2-trifluoroethyl)-9 fluorene-fluorene-9 monomethylamine, monohydrochloride

熔點· 1 4 5 - 1 5 0 °C MS (電噴霧，一離子）m/z 686 (M + H) 訂 經濟部中央標準局員工消費合作社印製 實例3 9Melting point · 1 4 5-1 5 0 ° C MS (electrospray, one ion) m / z 686 (M + H) Order Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Example 3 9

CICI

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）—318 - 實例4 0 $ 486469 A7 B7 五、發明説明（316 ) 9 —〔4 —〔4 一〔〔 〔2 -（4 一氯苯基）一 3 — II 比陡 基）羰基〕胺基〕—1—哌淀基〕丁基〕一 N -（2，2 ，2 —三氟乙基）—9H —芴一 9 一甲醯胺，二氫氯酸鹽 MS (ESI - NH3，+ 離子）（M + H) 661。 (請先閲讀背面之注意事項再填寫本頁) N — (2 ，2 ，2 —三氟乙基）一9 一〔4 一〔4 —〔〔 〔2 —〔 （3，3，3 -三氟丙基）硫基〕一 3 — Ditii定基 〕鑛基〕胺基〕一 哌陡基〕丁基〕一 9H -荀一 9 — 甲醯胺，單氫氯酸鹽 MS(ESI-NH3，+離子）（M + H)679 經濟部中央標隼局員工消費合作社印製 實例4 1 $This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) —318-Example 4 0 $ 486469 A7 B7 V. Description of the invention (316) 9 — [4 — [4 1 [[[2-(4 1 Chlorophenyl) -3-II than acryl) carbonyl] amino] -1 -piperidinyl] butyl] -N-(2,2,2-trifluoroethyl) -9H -fluorene-9 9A Lamine, dihydrochloride MS (ESI-NH3, + ion) (M + H) 661. (Please read the notes on the back before filling out this page) N — (2, 2, 2 — trifluoroethyl) — 9 — [4 — [4 — [[[2 — [(3, 3, 3-3 Fluoropropyl) thio] thio-3-diitiyl] mine] amino] monopiperidyl] butyl] -9H-fluorene-9-formamidine, monohydrochloride MS (ESI-NH3, + Ion) (M + H) 679 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 4 1 $

含0 . 1 2莫耳乙醚 9 —〔 4 -〔 4 一〔〔 2 — ( 4 -吡啶基）苯醯〕胺基〕 本紙張尺度適用中國國家標準（CNS ) A4規格( 210X297公釐）_ 319 _ 一 486469 A7 ._B7___ 五、發明説明（3Π ) 一 1-吡啶基）丁基〕—N —（2，2，2 —三氟乙基） 一 9 Η —荀_ 9 一甲釀胺，二氫氯酸鹽 熔點· 140 — 150 °C (於115 °C下開始收縮） MS (電噴霧，—離子）m/z 627 (M + H) + 元素分析·〇37Η37Ρ3Ν4〇2+2Η(：ί + 2 · 1 4 Η 2 0之計算值： C，60.21;H，5.91;N，7.59 ;C 芡，9 · 6 0 ; F，7 · 7 2 實測值：C，6 0 · 2 1 ; Η，6 · 0 8 ; N，8 · 0 1 ;CJ?，9.23;F，7.37 (請先閲讀背面之注意事項再填寫本頁) 實例4 2Contains 0.12 mole ether 9 — [4-[4-[[2 — (4-pyridyl) phenyl hydrazine] amine group]] This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 319 _ One 486469 A7 ._B7 ___ V. Description of the invention (3Π) 1-pyridyl) butyl] —N — (2,2,2 —trifluoroethyl) — 9 Η — 荀 _ 9 Methylamine, Melting point of dihydrochloride · 140 — 150 ° C (shrink at 115 ° C) MS (electrospray, — ion) m / z 627 (M + H) + elemental analysis · 〇37Η37Ρ3Ν4〇2 + 2Η (: ί + 2 · 1 4 之 2 0 Calculated: C, 60.21; H, 5.91; N, 7.59; C 芡, 9 · 6 0; F, 7 · 7 2 Found: C, 6 0 · 2 1; Η, 6 · 0 8; N, 8 · 0 1; CJ ?, 9.23; F, 7.37 (Please read the precautions on the back before filling this page) Example 4 2

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

9 一〔4 一〔4 一〔 〔 （4，4^ —二氟基〔1 ，1^一 聯苯基〕—2 —基）羰基〕胺基〕一 1 一哌啶基〕丁基〕 —N —（2 ，2 ，2 —三氟乙基）一9H —芴一9一甲醯 胺，單氫氯酸鹽 熔點.1 3 1 - 3 4 °C MS (ESI ，+ 離子）m/z 6 6 2 ( Μ + Η ) 本紙張尺度適用中國國家標準（CNS ) Α4規格（21.0X297公釐）_ 320 486469 A7 B7 五、發明説明（318 ) 元素分析.C38H36F5N3〇2+HC^ + 1 · 7H2〇之 計算值：9 one [4 one [4 one [[(4,4 ^ —difluoro [1,1 ^ biphenyl] -2-yl) carbonyl] amino]] 1 1 piperidinyl] butyl] — N — (2,2,2—trifluoroethyl) -9H—fluorene-9-methaneamine, melting point of monohydrochloride. 1 3 1-3 4 ° C MS (ESI, + ion) m / z 6 6 2 (Μ + Η) This paper size applies to Chinese National Standard (CNS) A4 specification (21.0X297 mm) _ 320 486469 A7 B7 V. Description of the invention (318) Elemental analysis. C38H36F5N302 + HC ^ + 1 · Calculated value of 7H2〇:

本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐）__ 321 _ 486469 A7 B7 五、發明説明（319 ) 〕胺基〕_1 一哌啶基〕丁基〕一 9H —芴一 9 —甲醯胺 ，單氫氯酸鹽 MS (ESI ，+ 離子）m/z 6 6 3 ( Μ + Η )； (-離子）661 (Μ-Η) 元素分析· C34H36N4〇3F6.HC 义· 1 · 25Η2〇 • Ο · 1 2 H 5 C 2 0 C 2 Η 5 之計算值： C，56.69;H，5.62;N，7.67 ;C 芡，4 . 8 5 ; F ， 1 5 · 6 0 實測值：C，56.98;H，5.52;N，7.63 ;Cj?，4.74;F，15.31 (請先閱讀背面之注意事項再填寫本頁) 眚例4 5 $This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 0X297 mm) _ 321 _ 486469 A7 B7 V. Description of the invention (319)] Amine] _1-piperidinyl] butyl] -1H 9-formamidine, monohydrochloride MS (ESI, + ion) m / z 6 6 3 (Μ + Η); (-ion) 661 (Μ-Η) elemental analysis · C34H36N4〇3F6.HC meaning · 1 · 25Η2〇 • 〇 · 1 2 H 5 C 2 0 C 2 Η 5 Calculated value: C, 56.69; H, 5.62; N, 7.67; C 芡, 4. 8 5; F, 1 5 · 6 0 Measured Value: C, 56.98; H, 5.52; N, 7.63; Cj ?, 4.74; F, 15.31 (Please read the notes on the back before filling this page) 眚 Example 4 5 $

經濟部中央標準局員工消費合作社印製 9 —〔4 一〔4 一〔〔 （4 一氯基〔1 ，1 一聯苯基〕一 2 —基）羰基〕胺基〕一 1—哌啶基〕丁基〕一 N -（2 ，2 ，2 —三氟乙基）一 9H —芴—9 —甲醯胺，單氫氯 酸鹽Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China. 9— [4— [4 — [[(4-Cloyl [1,1biphenyl] —2-yl) carbonyl] amino] —1-piperidinyl 〕 Butyl] -N-(2,2,2-trifluoroethyl) -9H-fluorene-9-methaneamine, monohydrochloride

熔點· 1 2 3 — 1 2 8 °C MS (電噴霧，一離子）m/z 661 (M + H) 實例4 6 $ 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）_ M2 - 486469 A7 B7 五、發明説明（32〇 )Melting point · 1 2 3 — 1 2 8 ° C MS (electrospray, one ion) m / z 661 (M + H) Example 4 6 $ This paper size is applicable to China National Standard (CNS) A4 specification (21.0X297 mm) _ M2-486469 A7 B7 V. Description of the invention (32〇)

含有：0 · 8 Η 20 9 -〔4 一〔4 —〔〔 〔2 —（1 一甲基乙氧基）一3 — 吡啶基〕羰基〕胺基〕一 1 一哌啶基〕丁基〕一 Ν -（ 2 ，2 ，2 —三氟乙基）一 9Η —芴一 9-甲醯胺，單氫氯 酸鹽 MS (ESI ，+ 離子）m/z 6 0 9 ( Μ + Η )； (一離子）607 (Μ - Η) 元素分析· C34H39N4〇3F3· HCj? · 0 · 8Η2〇之 計算值ι C，61.9 1;H，6.36;N，8.49 ;C5，5.38;F，8.64 實測值：C，6 1 · 6 3 ; Η，6 · 4 5 ; Ν，8 · 3 1 經濟部中央標準局員工消費合作社印製 ;C 又，5-80;F，8.50Contains: 0 · 8 Η 20 9-[4-[4- — [[[2- (1 -methylethoxy)-3-pyridyl] carbonyl] amino] -1 -piperidinyl] butyl] -N- (2,2,2-trifluoroethyl) -9Η- 芴 -9-formamidine, monohydrochloride MS (ESI, + ion) m / z 6 0 9 (M + Η); (Ion) 607 (Μ-Η) Elemental analysis · Calculated value of C34H39N4〇3F3 · HCj? · 0 · 8Η2〇 C, 61.9 1; H, 6.36; N, 8.49; C5, 5.38; F, 8.64 Measured value : C, 6 1 · 6 3; Η, 6 · 4 5; Ν, 8 · 3 1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs; C, 5-80; F, 8.50

•1.65 HCI Nv_• 1.65 HCI Nv_

(請先閲讀背面之注意事項再填寫本頁) 實例4 7 $ cf3 本紙張尺度適用中國國家標準（cns ) A4規格（2ιοί297公釐)一 323 - 486469 A 7 B7 五、發明説明（321 ) 含有：1 . 5 Η 2〇 9 —〔4 一〔4 一〔〔 （2 —〔 （1 一甲基乙基）硫基〕 一 3 —吡啶基〕羰基〕胺基〕一 1 一哌啶基〕丁基〕一 Ν 一（2 ，2 ，2 —三氟乙基）一 9Η —荀一 9 一甲醯胺， 二氫氯酸鹽 MS (ESI ，+ 離子）m/z 6 2 5 ( Μ + Η )； (一離子）6 2 3 ( Μ — Η ) 元素分析· C34H39N402SF3· 1 · 65HC5 · 1 · 5 Η 2 0之計算值： C，57.36;H，6.18;N，7.87 ;C^，8.22;F，8.01; S，4 · 5 0 實測值·· C，5 7 · 5 6 ; H，6 · 3 7 ; N，7 · 7 4 ;Cj?，8.12;F，8.06; S ，4 · 4 7 實例4 8 $(Please read the precautions on the back before filling this page) Example 4 7 $ cf3 This paper size applies Chinese National Standard (cns) A4 specification (2ιοί297 mm) one 323-486469 A 7 B7 V. Description of the invention (321) Contains : 1.5 Η 209— [4— [4 — [[(2 -— ((1-methylethyl) thio] —3-pyridyl] carbonyl] amino]]-1—piperidinyl] Butyl] -N mono (2,2,2-trifluoroethyl)-9Η- 荀 -9-methaneamine, dihydrochloride MS (ESI, + ion) m / z 6 2 5 (Μ + Η); (one ion) 6 2 3 (Μ — Η) Elemental analysis · C34H39N402SF3 · 1 · 65HC5 · 1 · 5 Η 2 0 Calculated value: C, 57.36; H, 6.18; N, 7.87; C ^, 8.22 ; F, 8.01; S, 4 · 50 0 found · C, 5 7 · 5 6; H, 6 · 3 7; N, 7 · 7 4; Cj ?, 8.12; F, 8.06; S, 4 · 4 7 Examples 4 8 $

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 含有2 · 14莫耳H2〇 有效分子量=738· 105 本紙張尺度適用中國國家標準（〇奶）八4規格（21_0\297公釐）_ 324 _ 486469 A7 B7 五、發明説明（322 ) 9 —〔4 一〔4 -〔 〔2 — (3 -吡啶基）苯醯〕胺基〕 一 1—哌啶基〕丁基一 N — (2，，2，2 —三氟乙基） —9 Η —荀一 9 一甲釀胺，一氨氯酸鹽 熔點· 1 20 — 1 30 °C (於1 1 0°C下開始收縮） MS (電噴霧，一離子）m/z (M + H) + = 627 元素分析· C37H37F3N4〇2· 2HC又· 2 · 1 4 Η 2〇之計算值： C，60.21;H，5.91;N，7.59 ;Cj? ，9.60;F，7.72 實測值：C，6 0 · 2 6 ; Η，6 · 2 6 ; N，7 · 0 4 ;Cj?，9.09;F，7.15Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Contains 2 · 14 Molar H2 0 Effective molecular weight = 738 · 105 This paper applies Chinese national standards (〇 奶) Specification (21_0 \ 297 mm) _ 324 _ 486469 A7 B7 V. Description of the invention (322) 9 — [4-[4-[[2 — (3-pyridyl) phenylhydrazine] amine]] 1-piperidine Group] Butyl-N — (2,2,2,2-trifluoroethyl) —9 Η — 荀 -9 Methylamine, Melamine Melting point · 1 20 — 1 30 ° C (at 1 1 Shrinking at 0 ° C) MS (Electrospray, Ion) m / z (M + H) + = 627 Elemental Analysis · C37H37F3N4〇2 · 2HC and · 2 · 1 4 Η 2〇 Calculated value: C, 60.21 ; H, 5.91; N, 7.59; Cj ?, 9.60; F, 7.72 found: C, 6 0 · 2 6; Η, 6 · 2 6; N, 7 · 0 4; Cj ?, 9.09; F, 7.15

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 9 一〔4_〔4 一〔 （〔1，1—聯苯基〕一 4 —基鐵基 )胺基〕—1—哌啶基〕—3，3-二氟丁基〕—N -( 2 ，2 ，2 —三氟乙基）一 9H —荀一 9 —甲醯胺，N — 氧化物Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 9 1 [4_ [4 1 [([1,1-Biphenyl] -4-Ironyl)) ] -1-piperidinyl] -3,3-difluorobutyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-methaneamine, N-oxide

熔點· 185 - 188 °C MS (電噴霧）（M + H)+ 642; 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 325 一 486469 A7 B7 五、發明説明（323 ) (Μ — Η ) 一 6Melting point · 185-188 ° C MS (Electrospray) (M + H) + 642; This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _325 one 486469 A7 B7 V. Description of the invention (323) (Μ — Η) a 6

本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ 326 一 486469 A7 B7 五、發明説明（324 ) 實例5 2 #This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 326 486469 A7 B7 V. Description of the invention (324) Example 5 2 #

9 一〔4 一〔4一〔〔 （3，6 —二氯基—2 — Dtiu定基） 羰基〕胺基〕一 1 一哌啶基〕丁基〕—N —（ 2，2，2 一三氟乙基）一9H—芴一9一甲醯胺，單氫氯酸鹽 MS (電噴霧，+ 離子）m/z 6 19 ( M + Η ) 〔2 C5同位素型式〕 實例5 3 $ (請先閱讀背面之注意事項再填寫本頁)9 one [4 one [4 one [[(3,6-dichloro-2 — Dtiu amidyl) carbonyl] amino]] 1 1 piperidinyl] butyl] —N — (2, 2, 2 one three Fluoroethyl)-9H-fluorene-9-methylamidine, monohydrochloride MS (electrospray, + ion) m / z 6 19 (M + Η) 〔2 C5 isotope pattern〕 Example 5 3 $ (Please (Read the notes on the back before filling out this page)

經濟部中央標準局員工消費合作社印製 9*一〔4—〔4-〔〔2—（四氫基-2-合氧基一21^ 一 1 ，3 —噁嗪—3 -基）苯醯〕胺基〕—1 一哌啶基〕 丁基〕—N -（2，2，2 -三氟乙基）一 9H —芴一 9 一甲醯胺，單氫氯酸鹽 實例5 4 $ 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X 297公釐）—327 - — 486469 A7 B7 五、發明説明（325 )Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China 9 * 一 [4-—4-[[2- (tetrahydro-2-oxyl 21 ^ -1 1,3-oxazin-3-yl) benzene ] Amine]-1-piperidinyl] Butyl] -N-(2,2,2-trifluoroethyl)-9H-fluorene-9-methylamine, monohydrochloride Example 5 4 $ this Paper size applies to Chinese National Standard (CNS) A4 specification (21.0X 297 mm) — 327 — — 486469 A7 B7 5. Description of the invention (325)

9 一〔4 一〔4 一〔〔 （5 -氯基一 2 -噻嗯基）羰基〕 胺基〕一 1 一哌啶基〕丁基〕一 N -（ 2，2，2 -三氟 乙基）—9H—芴一9一甲醯胺，單氫氯酸鹽 MS (ESI ，+ 離子）m/z 5 9 0 ( Μ + Η ) 1 同位素型式 元素分析· C3OH31N302C^SF3.HC^· 0 . 6H2〇· 〇 · 2H5C2〇C2H5之計算值： C，56.72;H，5.4 4;N，6.44 ;Cj?，10.87;F，8.74; S，4 . 9 2 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 實測值：C，5 6 · 4 3 ; Η，5 · 3 7 ; N，6 · 3 8 ;C^，10.70;F，8.73; S，5 · 3 6 實例5 5 $ 本紙張尺度適用中國國家標準（CNS ) A4規格（21.0X297公釐）_ 328 486469 A7 B7 五、發明説明（326 )9 1 [4 1 [4 1 [[(5-chloro- 2-thienyl) carbonyl] amine]] 1 -piperidinyl] butyl] -N-(2,2,2-trifluoroethyl Group) —9H—fluorene-9-methylamidine, monohydrochloride MS (ESI, + ion) m / z 5 9 0 (Μ + Η) 1 isotopic pattern elemental analysis · C3OH31N302C ^ SF3.HC ^ · 0 Calculated values of 6H2〇 · 2H5C2〇C2H5: C, 56.72; H, 5.44; N, 6.44; Cj ?, 10.87; F, 8.74; S, 4. 9 2 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the precautions on the back before filling this page) Measured value: C, 5 6 · 4 3; Η, 5 · 3 7; N, 6 · 3 8; C ^, 10.70; F, 8.73; S, 5 · 3 6 Example 5 5 $ This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21.0X297 mm) _ 328 486469 A7 B7 V. Description of the invention (326)

9 一〔 4 一〔 4 - .〔〔 2 -氟基—5 -（三氟甲基）苯醯 〕胺基〕一 1—哌B定基〕丁基〕一 N —（2，2，2 -三 氟乙基）- 9H —芴-9-甲醯胺，單氫氯酸鹽 (M + H) + 636; (Μ - Η) - 6 3 49 1 [4 1 [4-. [[2 -Fluoro-5-(trifluoromethyl) phenylhydrazone] amino] -1-piperidinyl] butyl] -N-(2,2,2- (Trifluoroethyl)-9H —fluorene-9-formamidine, monohydrochloride (M + H) + 636; (Μ-Η)-6 3 4

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 9 一〔4 一〔4 一〔 （5 -氯基一 2 —甲氧基苯醯）胺基 〕—1-哌啶基〕丁基〕一 N -（2，2，2 -三氟乙基 )一 9H -芴一 9—甲醯胺，單氫氯酸鹽 熔點· 1 0 8 - 1 1 3 °C MS (電噴霧，一離子）m/z 615 (Μ十Η) 實例5 7 * 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ 329 - 486469 A7 B7 五、發明説明（327 )(Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China 9-[4-[4-[(5 -Chloro-1 -methoxymethoxyphenyl) amino]- 1-piperidinyl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-methylamine, melting point of monohydrochloride · 1 0 8-1 1 3 ° C MS (Electrospray, Ion) m / z 615 (Μ 十 Η) Example 5 7 * This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ 329-486469 A7 B7 V. Description of the invention ( 327)

含有：H2〇.〇.15H5C2〇C2H5 9一〔4一〔4 一〔〔 （2，2&gt;- 二噻吩—5 -基）羰 基〕胺基〕胺基〕一 1 -哌啶基〕丁基〕一 N -（ 2，2 ，2 —三氟乙基）一 9 Η -芴一 9 一甲醯胺，單氫氯酸鹽 MS (ESI ，+ 離子）m/z 6 3 8 ( Μ + Η ) 元素分析· c34h34n3〇2s2f3· HC义· h2〇· 0.15H5C2〇C2H5之計算值： C，59.08;H，5.52;N，5.97 ;Cj?，5.04;F，8.10; S，9 · 1 2 實測值：C ，5 8 · 8 8 ; H，5 · 4 1 ; N，5 · 9 0 ;Cj?，4.97;F，8.24; 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) S ，9 · 2 2 實例5 8 'Contains: H20.0.15H5C2OC2H5 9- [4- [4-[[(2,2 &gt; -dithiophene-5-yl) carbonyl] amino] amine]] 1-piperidinyl] butyl ] -N- (2,2,2-trifluoroethyl) -9 Η- 芴 -9-methylamine, monohydrochloride MS (ESI, + ion) m / z 6 3 8 (Μ + Η ) Elemental analysis · c34h34n3〇2s2f3 · HC meaning · h2〇 · 0.15H5C2〇C2H5 calculated values: C, 59.08; H, 5.52; N, 5.97; Cj ?, 5.04; F, 8.10; S, 9 · 1 2 Measured Value: C, 5 8 · 8 8; H, 5 · 4 1; N, 5 · 9 0; Cj ?, 4.97; F, 8.24; Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the note on the back first) Matters need to be refilled on this page) S, 9 · 2 2 Example 5 8 ′

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 330 一 486469 A7 B7 五、發明説明（328 ) (請先閱讀背面之注意事項再填寫本頁) 9_〔4一〔4一〔 〔2 —（苯基甲胺基）苯醯〕胺基〕 —1 一哌啶基〕丁基〕一 N -（2，2，2 -三氟乙基） 一9H—芴一9一甲醯胺，單氫氯酸鹽 ESI (M + H) + 6 5 5 實例5 9 $This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm)-330-486469 A7 B7 V. Description of invention (328) (Please read the notes on the back before filling this page) 9_ 〔4 一 〔4 一[[2- (phenylmethylamino) phenylhydrazone] amino]-1-piperidinyl] butyl] -N-(2,2,2-trifluoroethyl)-9H-fluorene 9-1 Amidine, monohydrochloride ESI (M + H) + 6 5 5 Example 5 9 $

9 —〔4 -〔4 一〔〔 （3 -氯基苯並〔b〕噻吩-2 -基）羰基〕胺基〕一 1 一哌啶基〕丁基〕一 N -（ 2，2 ，2 —三氟乙基）—9H —芴一 9 —甲醯胺，單氫氯酸鹽 MS (ESI ，+ 離子）m/z 6 4 0 ( Μ + Η ) 1 C j?同位素型式 經濟部中央標準局員工消費合作社印製 實例6 0 $9 — [4-[4-[[(3-Chlorobenzo [b] thiophen-2-yl) carbonyl] amino] -1 1-piperidinyl] butyl] -N- (2, 2, 2 —Trifluoroethyl) —9H —fluorene-9 —methaneamine, monohydrochloride MS (ESI, + ion) m / z 6 4 0 (Μ + Η) 1 C j? Isotope type central standard of the Ministry of Economy Bureau employee consumer cooperative printing example 6 0 $

9 一〔4 一〔4一〔 〔 （3，4 一二氯基一 2 —噻嗯基） 羰基〕胺基〕一 1 一哌啶基〕丁基〕—N -（ 2，2，2 本紙張尺度適用中國國家標準（〇奶）八4規格（210'/297公釐）_331 一 486469 A7 B7 五、發明説明（329 ) 一三氟乙基）一 9 Η —苟一 9 一甲醯胺，單氫氯酸鹽 熔點·1 1 0 — 1 20°C (於9 5°C下開始收縮） MS (電噴霧，一離子）m/z (M + H) 624 ; 2 Cj?同位素型式 實例6 1 *9 1 [4 1 [4 1 [[(3,4 -dichloro- 2-thienyl) carbonyl] amino]-1 -piperidinyl] butyl] -N-(2, 2, 2 Paper size applies to Chinese national standard (0 milk) 8 (210 '/ 297 mm) _331 one 486469 A7 B7 V. Description of the invention (329) trifluoroethyl) 9 9 Η — Gou 9 9 methylamine , Monohydrochloride melting point · 1 1 0 — 1 20 ° C (shrink at 95 ° C) MS (electrospray, one ion) m / z (M + H) 624; 2 Cj? Isotopic pattern example 6 1 *

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 反式一 9 一〔4 一〔4 —〔〔（2 -苯基環丙基）羰基〕 胺基〕-1 一哌啶基〕丁基〕一 N— (2，2，2 -三氟 乙基）一9H—芴一9一甲醯胺，單氫氯酸鹽 熔點.1 1 8 - 1 2 6 °C MS (電噴霧，一離子）m/z 5 9 0 ( M + Η ) 元素分析· C35H38F3N3O2+HCj? + 0 · 82Η2〇 + 0 . 36二噁烷之計算值： C，65.07;H，6.52;N，6.25 ;Cj?，5.27;F，8.47 實測值·· C，6 5 · 0 7 ; Η，6 · 5 0 ; N，6 · 1 2 ;Cj?，5.36;F，8.25 實例6 2 $(Please read the precautions on the back before filling out this page) The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs printed trans-9 9 [4 1 [4 — [[(2-phenylcyclopropyl) carbonyl] amine] -1 monopiperidinyl] butyl] -N- (2,2,2-trifluoroethyl)-9H-fluorene-9-methylamine, melting point of monohydrochloride. 1 1 8-1 2 6 ° C MS (Electrospray, Ion) m / z 5 9 0 (M + Η) Elemental analysis · C35H38F3N3O2 + HCj? + 0 · 82Η2〇 + 0. 36 Calculated value of dioxane: C, 65.07; H, 6.52; N, 6.25; Cj ?, 5.27; F, 8.47 Measured values · C, 6 5 · 0 7; Η, 6 · 5 0; N, 6 · 1 2; Cj ?, 5.36; F, 8.25 Example 6 2 $

本紙張尺度適用中國國家標準（CNS)A4規格（210X297公釐）一 332 - 486469 A7 B7 五、發明説明（33〇 )This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1 332-486469 A7 B7 V. Description of invention (33)

9_〔4 -〔4一〔 〔 〔4 一氯基—4 / 一（三氟甲基） 〔1 ，1 一聯苯基〕一 2-基）羰基〕胺基〕一 1 一哌啶9_ [4-[4-[[[4- monochloro-4 / mono (trifluoromethyl) [1,1 biphenyl]-2-yl) carbonyl] amine]] 1 1 piperidine

基〕丁基〕一 N -（2，2，2 —三氟乙基）一 9H -芴 一 9 —甲醯胺，單氫氯酸鹽 熔點.123 - 12 8 °C MS (電噴霧，一離子）m/z 7 2 8 ( M + Η ) 元素分析· C39H36Cj2F6N302+HC 5 + Ο · 5H2〇之計算值： C，60.55;H，4.95;N，5.43 ;C 又，9 · 1 7 實測值：C，60.54;H，4.84;N，5.22 ;C 又，8 · 9 1 實例6 3 $Yl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-formamide, melting point of monohydrochloride. 123-12 8 ° C MS (electrospray, a Ion) m / z 7 2 8 (M + Η) Elemental analysis · C39H36Cj2F6N302 + HC 5 + Calculated value of 5H2〇: C, 60.55; H, 4.95; N, 5.43; C, 9 · 1 7 Measured value : C, 60.54; H, 4.84; N, 5.22; C, 8 · 9 1 Example 6 3 $

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 9 —〔4 —〔4 一〔 〔 〔4 一 氯基一 4&gt; —(三氟甲基） 〔1 ，1 &gt; 一聯苯基〕一 2 —基）羰基〕胺基〕一 1—哌 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 333 — 486469 A7 _B7_ 五、發明説明（331 )Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 9 — [4 — [4 a , 1 &gt; monobiphenyl]-2 -yl) carbonyl] amine]-1-piper paper size applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) _ 333 — 486469 A7 _B7_ V. Description of the invention (331)

啶基〕丁基〕一 N —（2，2，2 —三氟乙基）一 9H — 芴一9一甲醯胺，N—氧化物 熔點· 142 - 144 °C MS (電噴霧，一離子）m/z 743 (M + H) 元素分析· C39H36Cj?F6N3〇3+〇 · 88H2〇之計 算值： C，61.63;H，5.01;N，5.53 ;C 又，4 · 6 6 實測值：C，61.64;H，5.05;N，5.42 ;C 又，5 · 0 2 (請先閱讀背面之注意事項再填寫本頁) 實例6 4Pyridyl] butyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9-methylamine, N-oxide melting point · 142-144 ° C MS (Electrospray, Ion ) M / z 743 (M + H) Elemental analysis · Calculated value for C39H36Cj? F6N3〇3 + 〇 88H2〇: C, 61.63; H, 5.01; N, 5.53; C, 4 · 6 6 Found: C , 61.64; H, 5.05; N, 5.42; C, 5 · 0 2 (Please read the precautions on the back before filling this page) Example 6 4

經濟部中央標準局員工消費合作社印製 9 一〔4 一〔4一〔 （2 —吡啶基苯醯）胺基〕一 1—哌 啶基〕丁基〕一 N — (2，2，2 -三氟乙基）一 9H -芴一 9 一甲醯胺，N —氧化物，二氫氯酸鹽 MS ( M + Η ) + 643; (Μ- Η) - 6 4 1 元素分析· C37H37F3N4〇3十2HCj? + 1 · 9 4 Η 2 0之計算值： C，59.21; Η，5·76;Ν，7.46 本紙張尺度適用中國國家標準（CNS ) Α4規格（2丨0X297公釐）一 334 一 486469 A7 B7 五、發明説明（332 ) ;F，7 · 5 9 ；C J2 ，9 .4 Σ 實測值：0，59· 6 1 ；Η y 5 · 8 1 ; ；N ’ ，7 _ .2 ;F ，7 · 1 9 ；C ，9 • 0 f 實例6 5 $Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 9-[4-[4-[(2-pyridylphenylhydrazone) amine]-1-piperidinyl] butyl]-N-(2, 2, 2- Trifluoroethyl) -9H-fluorene-9 monomethylamine, N-oxide, dihydrochloride MS (M + Η) + 643; (Μ- Η)-6 4 1 elemental analysis · C37H37F3N4〇3 10 2HCj? + 1 · 9 4 之 2 0 Calculated values: C, 59.21; Η, 5.76; N, 7.46 This paper size applies to China National Standard (CNS) Α4 specifications (2 丨 0X297 mm)-334- 486469 A7 B7 V. Description of the invention (332); F, 7 · 5 9; C J2, 9.4 Σ Measured value: 0, 59 · 6 1; Η y 5 · 8 1;; N ', 7 _ .2 ; F, 7 · 1 9; C, 9 • 0 f Example 6 5 $

經濟部中央標隼局員工消費合作社印製 N - ( 2 ， 2 ，2 —三氟乙基） -9 一 4 C 4 一〔〔 〔1 -〔 C 4 一（三氟甲基）苯基〕 甲 基 ] 一 2 一 哌啶基 〕羰基〕 胺基 〕一 1 一 哌啶基〕 丁基 ) 一 9 Η — 芴 -9 一 甲醯胺， 二氫氯酸鹽 M S ( E S +離子） m / Z 7 1 5 C Μ + Η ] 元素分析 • C 3 9 Η 4 4 F 6n 4 〇 2 + 2 Η 2 〇 + 2 Η C 5之計 算值： C j 5 6.8 7 ； Η， 6 · 1 2 &gt; Ν 6 .8 0 實測值： C 5 7.0 1 ； Η ， 6 . 0 1 Ν 6 .7 4Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, N-(2, 2, 2, 2-trifluoroethyl) -9-4 C 4-[[[1-[C 4-(trifluoromethyl) phenyl]] (Methyl)-2-piperidinyl] carbonyl] amine]-1-piperidinyl] butyl)-9 Η — 芴 -9 monomethylamine, dihydrochloride MS (ES + ion) m / Z 7 1 5 C M + Η] Elemental analysis • C 3 9 Η 4 4 F 6n 4 〇2 + 2 Η 2 〇 + 2 Η Calculated value of C 5: C j 5 6.8 7; Η, 6 · 1 2 &gt; Ν 6 .8 0 found: C 5 7.0 1; Η, 6. 0 1 Ν 6 .7 4

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 335 _ 裝 訂 (請先閲讀背面之注意事項再填寫本頁) 486469 A7 _ B7 _ 五、發明説明（333 ) N —〔1一〔4 —〔9 —〔 〔 （2，2，2 —三氣乙基） 胺基〕羰基〕一 9H -芴一 9 —基〕丁基〕_4 一哌啶基 〕一 2 -吡啶甲醯胺，N —氧化物，二氫氯酸鹽 M S ( M + Η ) + @ 567; (Μ - Η)-@ 565; (2 Μ + Η ) + @ 113 3 元素分析· C 3 χ Η 3 3 F 3 N 4 〇 3 + 2 H C iT 十 1 · 7 Η 2 〇 之計算值： C，55.56;H，5.78; Ν，8·36 ;F，8.50;C^，10.58 實測值：C，5 5 · 8 9 ; Η，5 · 8 1 ; N，8 · 1 8 ;F，8.66;Cj?，10.18 實例6 7 *This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) _ 335 _ Binding (please read the precautions on the back before filling this page) 486469 A7 _ B7 _ V. Description of the invention (333) N — [1 [[4 — [9 — [[(2,2,2 —trifluoroethyl) amino] carbonyl]] 9H-fluorene-9-yl] butyl] -4 4-piperidinyl]] 2-pyridinemidine Amine, N-oxide, dihydrochloride MS (M + Η) + @ 567; (Μ-Η)-@ 565; (2 Μ + Η) + @ 113 3 Elemental analysis · C 3 χ Η 3 3 F 3 N 4 〇3 + 2 HC iT Calculated value of 1 · 7 Η 2 〇: C, 55.56; H, 5.78; Ν, 8.36; F, 8.50; C ^, 10.58 Found: C, 5 5 · 8 9; Η, 5 · 8 1; N, 8 · 1 8; F, 8.66; Cj ?, 10.18 Example 6 7 *

經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 反式一 9 一〔4一〔4 一〔〔2 -（2 -苯並瞎唑基）苯 醯〕胺基〕一 1-哌啶基丁基〕一 N — (2，2，2 -三 氟乙基）—9H -芴-9 一甲醯胺，N —氧化物 MS(M + H) + @ 6 9 9； 697 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）—336 _ 486469 A7 B7 五、發明説明（334 ) 元素分析· C39H37F3N4〇3S + 1 · 5H2〇 + Ο . 3 C 6H 14之計算值： C &gt; 6 5 , .1 9 ；Η， 5 . 9 3 ; N， 7 . 45 t F 7 · .5 8 ;C艾 ，4 • 2 7 實測值：C 6 5 . .1 2 ；Η， 5 . 8 5 1 N， 7 _ .29 t F ， 7 _ .2 3 ;C义 ，4 2 9 實例6 8 $Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) trans one 9 one [4 one [4 one [[2-(2 -benzobenzozolyl) benzene 醯] Amine] -1-piperidinylbutyl] -N — (2,2,2-trifluoroethyl) —9H —fluorene-9 monomethylamine, N —oxide MS (M + H) + @ 6 9 9; 697 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) —336 _486469 A7 B7 V. Description of the invention (334) Elemental analysis · C39H37F3N4〇3S + 1 · 5H2〇 + 〇 3 Calculated value for C 6H 14: C &gt; 6 5, .1 9; Η, 5. 9 3; N, 7. 45 t F 7 · .5 8; C Ai, 4 • 2 7 Found: C 6 5 . .1 2; Η, 5. 8 5 1 N, 7 _ .29 t F, 7 _. 2 3; C meaning, 4 2 9 Example 6 8 $

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 基〕羰基〕胺基〕一 1 一哌啶基〕丁基〕一 N -（2，2 ，2 —三氟乙基）一 9H —芴一 9 一甲醯胺，二氫氯酸鹽 MS (ES，+ 離子）m/z 653 〔M + H〕 兀素分析· C38H53Cj?2F3N4〇2+ 1 · 5H2〇之5十 算值： C，60.63;H，7.50;N，7.44 ;F，7.57;Cj?，9.42 實測值·· C，6 0 . 7 3 ; Η，7 · 7 4 ; N，7 · 6 5 ;F，7.22;Ci，9.85 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）__ 337 _ 486469 A7 B7 五、發明説明（335) 實例6 9(Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs] Carbonyl] Amine]-1 Piperidinyl] Butyl]-N-(2, 2, 2 — Trifluoroethyl)-9H —fluorene-9 monomethylamine, dihydrochloride MS (ES, + ion) m / z 653 〔M + H〕 Element analysis · C38H53Cj? 2F3N4〇2 + 1 · 5H2 Calculated value of 50: C, 60.63; H, 7.50; N, 7.44; F, 7.57; Cj ?, 9.42 Measured value · C, 6 0. 7 3; 7, 7 · 7 4; N, 7 · 6 5; F, 7.22; Ci, 9.85 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 337 _ 486469 A7 B7 V. Description of the invention (335) Example 6 9

經濟部中央標準局員工消費合作社印製 N —（2，2 ，2 —三氟乙基）一9 —〔4 -〔4 -〔〔 〔1 一（ 3，3，3 -三氟丙基）一 2 -哌啶基〕羰基〕 胺基〕—1 一哌啶基〕丁基〕一 9H —芴一 9 一甲醯胺， 二氫氯酸鹽 MS (ES，+ 離子）m/z 653〔M + H〕 元素分析.C34H44CJ?2F6N4〇2+1 . 5H2〇之計 算值= C，54.26;H，6.2 9;N，7.44 ;F，1 5 · 1 4 實測值：C，5 4 · 4 0 ; Η，6 · 2 1 ; N，7 . 3 8 ;F，1 5 · 5 3 實例7 0 $Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs N— (2,2,2-trifluoroethyl) —9— [4-[4-[[[1 1 (3,3,3 -trifluoropropyl) Mono-2-piperidinyl] carbonyl] amino] -1 monopiperidinyl] butyl] -9H-fluorene-9 monomethylamine, dihydrochloride MS (ES, + ion) m / z 653 [ M + H] Elemental analysis. C34H44CJ? 2F6N4〇2 + 1. Calculated value of 5H2〇 = C, 54.26; H, 6.2 9; N, 7.44; F, 1 5 · 1 4 Found: C, 5 4 · 4 0; Η, 6 · 2 1; N, 7. 3 8; F, 1 5 · 5 3 Example 7 0 $

〇〇

MS (ESI ，+ 離子）m/z 551 (Μ 十 Η) (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS -338 - 486469 A7 B7 五、發明説明（336 ) 例 實MS (ESI, + ion) m / z 551 (Μ 十 Η) (Please read the precautions on the back before filling out this page) This paper size applies to Chinese national standards (CNS -338-486469 A7 B7) V. Description of the invention (336 ) Examples

Ν 基 乙 氟 三 (請先閲讀背面之注意事項再填寫本頁) 芴 I Η 9 7 IX 點 熔Ν, ethyl, trifluoro (Please read the precautions on the back before filling this page) 芴 I Η 9 7 IX

S E 析： 分值 素算 元計 醯胺°cm nx 苯醯 2 &gt; c 基甲 8 子32 碘 I 1 離 三 9 I + Η 基 啶 哌 I 1 鹽 I 酸 &gt;—V 氯 基氫 胺單 8 2 9 Ζ 2 〇 3 Ν 3 ο Η 基 之 〇 2 ΗSE analysis: Calciumamine ° cm nx Benzene 2 &gt; c Benzyl 8 ions 32 Iodine I 1 ion 3 9 I + hydrazidine I 1 salt I acid &gt; -V chlorohydroamine Single 8 2 9 Zn 2 〇3 Ν 3 ο Η 基 之 〇2 Η

C Η 4 Ν 2C Η 4 Ν 2

C 經濟部中央標隼局員工消費合作社印製 值 測 實 Η 4 ; 1 例 實 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）-339 - Ν 7 2 486469 A7 B7 五、發明説明（337 )C. Measurement of printed values by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 4; 1 case of this paper is applicable to China National Standard (CNS) A4 (210X297 mm) -339-Ν 7 2 486469 A7 B7 V. Invention Instructions (337)

1 : 1氫氯酸鹽 經濟部中央標準局員工消費合作社印製 9 一〔 4 一〔4一（苯醯胺基）一1一哌啶基〕丁基〕一 N —（2 ，2 ，2 —三氟乙基）一9H —瞎噸一 9-甲醯 胺，單氫氯酸鹽 熔或沸點· 145 - 150 °C MS (ES，+ 離子）m/z 5 8 2 ( Μ + Η ) 元素分析· C32H34N3〇2F3S + 1 · 0HC5 + Ο . 7 5 Η 2 0之計算值： C，60.94;H，5.67;N，6.6 6 ;F，9 · 0 4 實測值：C，6 0 · 9 7 ; H，6 . 0 0 ; N，6 . 2 6 ;F，9 · 1 5 實例73$至159# 下列化合物係藉下述之robotics步驟製得。 (請先聞讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（ CNS ) A4規格（210X297公釐）—34〇 _ 486469 A7 B7 五、發明説明（338 )1: 1 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics, Hydrochloride. 9-[4-[4-(phenylamido)-1-piperidinyl] butyl]-N — (2, 2, 2 —Trifluoroethyl) —9H —blind ton 9-formamidine, melting or boiling point of monohydrochloride · 145-150 ° C MS (ES, + ion) m / z 5 8 2 (Μ + Η) Elemental analysis · C32H34N3〇2F3S + 1 · 0HC5 + 0. Calculated value of 7 5 Η 2 0: C, 60.94; H, 5.67; N, 6.6 6; F, 9 · 0 4 Found: C, 6 0 · 9 7; H, 6. 0 0; N, 6. 2 6; F, 9 · 1 5 Examples 73 $ to 159 # The following compounds were prepared by the following robotics procedure. (Please read the precautions on the back before filling out this page) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm)-34〇_486469 A7 B7 V. Description of the invention (338)

Robotics 步駿 供製備醯胺用之Robotic法Robotics Robotic method for preparing amidine

請注意實例7 3*至1 5 9*中，對於氮上僅帶有兩個 單鍵鍵結取代基之結構方面，第三個取代基始終爲氫，但 其並未清楚地示於結構中。此外，請注意實例7 3 $至 1 5 9*中，有關帶有僅具一個單鍵鍵結取代基之氧及硫 之結構方面，第二個取代基始終爲氫，但其並未清楚地示 於結構中。 (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 341 - 486469 A7 B7 五、發明説明（339 ) 實例 7 3*Note that in the examples 7 3 * to 15 9 *, for the structure with only two single bond bonding substituents on the nitrogen, the third substituent is always hydrogen, but it is not clearly shown in the structure . In addition, please note that in the examples 7 3 $ to 1 5 9 *, regarding the structure with oxygen and sulfur having only one single bond substituent, the second substituent is always hydrogen, but it is not clear Shown in the structure. (Please read the notes on the back before filling this page.) Order the paper printed by the Central Consumers Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperatives. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 341-486469 A7 B7 (339) Example 7 3 *

m/z 694 (M+H) 5m / z 694 (M + H) 5

實例 7 4 m/z 672 (M+HExample 7 4 m / z 672 (M + H

(請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 10 m/z 659 (M+H)(Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 10 m / z 659 (M + H)

H3C、W—NH3C, W-N

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）_ Mg _ -CH, 486469 A7 B7 五、發明説明（340 ) m/z 595 (M+H) 5 實例This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) _ Mg _ -CH, 486469 A7 B7 V. Description of the invention (340) m / z 595 (M + H) 5 Examples

ο 實例 77*ο Example 77 *

(請先閱讀背面之注意事項再填寫本頁) m/z 654 (M+H)(Please read the notes on the back before filling this page) m / z 654 (M + H)

經濟部中央標準局員工消費合作社印製 10Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 10

O FO F

m/z 586 (M+H) 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 ^ 486469 A7B7 五、發明説明（341 ) 5 m/z 619 (M+H) 實例 7Q*m / z 586 (M + H) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 1 ^ 469 469 A7B7 V. Description of the invention (341) 5 m / z 619 (M + H) Example 7Q *

ΟΟ

α α 實例α α Examples

CH〇 (請先閲讀背面之注意事項再填寫本頁) m/z 610 (M+H) 經濟部中央標準局員工消費合作社印製 10 m/z 579 (M+H) 實例 81*CH〇 (Please read the notes on the back before filling this page) m / z 610 (M + H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 10 m / z 579 (M + H) Example 81 *

本紙張尺度適用中國國家標準（〇奶）八4規格（210'/297公釐）_ 344 _ 486469 A7 B7 五、發明説明（342 ) 啻例 82*This paper size is in accordance with Chinese National Standard (〇 奶) 8 4 specifications (210 '/ 297 mm) _ 344 _ 486469 A7 B7 V. Description of the invention (342) Example 82 *

O CHO CH

Ο &quot; Ο m/z 609 (Μ十Η) 5Ο &quot; Ο m / z 609 (Μ 十 Η) 5

實例 ftVExample ftV

(請先閱讀背面之注意事項再填寫本頁) m/z 565 (M+H) 實例 84* 經濟部中央標準局員工消費合作社印製 m/z 611 (M+H)(Please read the notes on the back before filling out this page) m / z 565 (M + H) Example 84 * Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs m / z 611 (M + H)

P S，、CH,P S ,, CH,

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）—_ 486469 A7 B7 五、發明説明（343 )This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) — 486469 A7 B7 V. Description of the invention (343)

m/z 710 (M+H) 5 實例 86,m / z 710 (M + H) 5 Example 86,

9 CH.9 CH.

(請先閱讀背面之注意事項再填寫本頁) m/z 553 (M+H) 經濟部中央標隼局員工消費合作社印製 10 m/z 556 (Μ+Η)(Please read the notes on the back before filling this page) m / z 553 (M + H) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 10 m / z 556 (Μ + Η)

Ο ΝΟ Ν

本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）_ 346 _ 486469 A7 B7 五、發明説明（344 )This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 346 _ 486469 A7 B7 V. Description of invention (344)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -347 - 486469 A7 B7 五、發明説明（345 ) 實例 Q1*This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -347-486469 A7 B7 V. Description of invention (345) Example Q1 *

m/z 693 (M+H) 實例 cn* (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製m / z 693 (M + H) Example cn * (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

10m/z 570 (M+H) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）348 486469 A7 B7 五、發明説明（346 ) 實例 94*10m / z 570 (M + H) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 348 486469 A7 B7 V. Description of invention (346) Example 94 *

m/z 677 (M+H) (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 實例 96*m / z 677 (M + H) (Please read the notes on the back before filling this page) Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Example 96 *

m/z 643 (M+H) 本紙張尺度適用中國國家標準（CNS)A4規格（210X297公釐）_ 349 _ 486469 A7 B7 五、發明説明（347 ) 實例 Q7:m / z 643 (M + H) This paper size applies to China National Standard (CNS) A4 (210X297 mm) _ 349 _ 486469 A7 B7 V. Description of the invention (347) Example Q7:

m/z 661 (M+H) 5 實例 QR*m / z 661 (M + H) 5 examples QR *

m/z 661 (M+H) 實例 99* (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 10 m/z 644 (M+H)m / z 661 (M + H) Example 99 * (Please read the precautions on the back before filling this page) Printed by the Employees' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs 10 m / z 644 (M + H)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）* 350 _ 486469 A7 B7 五、發明説明（348 ) mThis paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) * 350 _ 486469 A7 B7 V. Description of the invention (348) m

Η + (M 5 m Η 十 (ΜΗ + (M 5 m Η ((Μ

π3π3

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Η 十 Μ 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐） - 351 - 486469 A7 B7 五、發明説明（349 ) m/ (M- 5 m M- /(\十 Ten Μ This paper size applies to Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm)-351-486469 A7 B7 V. Description of the invention (349) m / (M- 5 m M- / (\

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本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 352 486469 A7 B7 五、發明説明（350 ) 賨例 10fi*This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 352 486469 A7 B7 V. Description of invention (350) Example 10fi *

m/z 683 (M+H) 5m / z 683 (M + H) 5

o s CCH3o s CCH3

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m/z 709 (M+H) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -353 - 486469 A7 B7 五、發明説明（351 ) m/ Η 十 (Μ 5 m/ Η 十 (Μm / z 709 (M + H) This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) -353-486469 A7 B7 V. Description of the invention (351) m / 十 十 (Μ 5 m / Η 十(Μ

αα

Br (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 ο 1 m Η 十 (ΜBr (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ο 1 m 十 十 (Μ

本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 354 - 486469 A7 B7 五、發明説明（352 )This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 354-486469 A7 B7 V. Description of invention (352)

0 F0 F

m/z 686 (M+H) 5 謇例 113*m / z 686 (M + H) 5 Example 113 *

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

m/z 678 (M+H 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）—355 486469 A7 B7 五、發明説明（353 ) 5 m/z 610 (M+H) 管例 114:m / z 678 (M + H Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs This paper is printed in accordance with Chinese National Standard (CNS) A4 (210X297 mm) —355 486469 A7 B7 V. Description of the invention (353) 5 m / z 610 (M + H) tube 114:

啻例 1151Example 1151

(請先閱讀背面之注意事項再填寫本頁) .¾衣. 訂 m/z 610 (M+H) 音例 116* 經濟部中央標準局員工消費合作社印製 10(Please read the notes on the back before filling out this page). ¾. Order m / z 610 (M + H) Example 116 * Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 10

0 m/z 610 (M+H)0 m / z 610 (M + H)

CL 'CK h3c&quot; 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）^ 356 _ 486469 A7 B7 五、發明説明（354 ) 實例 117* 5 10 m/z 638 (M+H) m/z 723CL 'CK h3c &quot; This paper size applies to China National Standard (CNS) A4 (210X297 mm) ^ 356 _ 486469 A7 B7 V. Description of the invention (354) Example 117 * 5 10 m / z 638 (M + H) m / z 723

(請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 •啻例 118*(Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs • Example 118 *

Cl m/z 589 (M+H) 357 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 486469 A7 B7 五、發明説明（355)Cl m / z 589 (M + H) 357-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 486469 A7 B7 V. Description of the invention (355)

m/z 638 (M+H) 5 m/z 638 啻例 Ywm / z 638 (M + H) 5 m / z 638 Example Yw

(請先閲讀背面之注意事項再填寫本頁) 衣. 訂 10 賨例 122* 經濟部中央標準局員工消費合作社印製(Please read the notes on the back before filling out this page) Clothing. Order 10 Example 122 * Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

m/z 565 (M+H) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ Οm / z 565 (M + H) This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) _ 〇

358 486469 A7 B7 五、發明説明（356 ) 實例 123*358 486469 A7 B7 V. Description of the Invention (356) Example 123 *

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m/z 596 (M+H) 5 眚例 124*m / z 596 (M + H) 5 Example 124 *

(請先閲讀背面之注意事項再填寫本頁) ·€衣- 訂 m/z 565 (M+H) 經濟部中央標準局員工消費合作社印製 10 m/z 653 賨例 125,(Please read the precautions on the back before filling out this page) · Clothes-Order m / z 565 (M + H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 10 m / z 653 Example 125,

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）__ 359 486469 A7 B7 五、發明説明（357 )This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) __ 359 486469 A7 B7 V. Description of the invention (357)

本紙張尺度適用中國國家標準（CNS)A4規格（210X297公釐）一 360 - 486469 A7 B7 五、發明説明（358 ) 賨例 Λ29*This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 360-486469 A7 B7 V. Description of the invention (358) Example Λ29 *

0 I CH, m/z 719 (M+H) 5 m/z 654 實例 130*0 I CH, m / z 719 (M + H) 5 m / z 654 instance 130 *

實例 131* (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 10Example 131 * (Please read the notes on the back before filling out this page) Order Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 10

m/z 680 (M+H) 〇 Οm / z 680 (M + H) 〇 〇

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）^ 361 486469 A7 B7 五、發明説明（359 ) 啻例 132:This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 361 486469 A7 B7 V. Description of the invention (359) Example 132:

m/z 704 (M+H) 5m / z 704 (M + H) 5

實例 133* m/z 699 (M+HExample 133 * m / z 699 (M + H

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m/z 733 (M+H) 0 sm / z 733 (M + H) 0 s

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 362 _ 教 486469 A7 B7 五、發明説明（36〇) 實例This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) _ 362 _ Teach 486469 A7 B7 V. Description of the invention (36〇) Example

m/z 617 (M+H) 5m / z 617 (M + H) 5

ClCl

(請先閲讀背面之注意事項再填寫本頁) m/z 652 (M+H) 經濟部中央標準局員工消費合作社印製 10 m/z 653 實例 137*(Please read the notes on the back before filling this page) m / z 652 (M + H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 10 m / z 653 Example 137 *

CHa 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 363 _ 486469 A7 B7 五、發明説明（361 ) 5 實例 1 3 ft *CHa This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1 363 _ 486469 A7 B7 V. Description of the invention (361) 5 Example 1 3 ft *

α m/z 668 (M+H)α m / z 668 (M + H)

二 NTwo N

(請先閲讀背面之注意事項再填寫本頁) 、訂 m/z 634 (M+H) 3tfiL 140*(Please read the notes on the back before filling this page), order m / z 634 (M + H) 3tfiL 140 *

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

N 10 m/z 634 (M+H) 本紙張尺度適用中國國家標年（CNS)A4規格（ 210X297公釐）^ 364 _ 486469 A7 B7 五、發明説明（362 ) 實例 141 *N 10 m / z 634 (M + H) This paper size is applicable to China National Standard Year (CNS) A4 (210X297 mm) ^ 364 _ 486469 A7 B7 V. Description of the invention (362) Example 141 *

00

m/z 635 (M+H) 5 實例 1 49*m / z 635 (M + H) 5 Examples 1 49 *

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(請先閲讀背面之注意事項再填寫本頁) m/z 655 (M十H) 經濟部中央標準局員工消費合作社印製 10 m/z 617 (M+H) 實例 143*(Please read the notes on the back before filling this page) m / z 655 (M / 10H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 10 m / z 617 (M + H) Example 143 *

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本紙張尺度適用中國國家標準（CNS ) A4規格（2l〇X297公釐）二3阳 486469 A7 B7 五、發明説明（363 ) 經濟部中央標準局員工消費合作社印製 ο i§This paper size applies to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 2 3 Yang 486469 A7 B7 5. Description of the invention (363) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ο i§

(請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 366 486469 A7 B7 五、發明説明（364 ) 1 ’ 啻例 1 47*(Please read the precautions on the back before filling this page) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 366 486469 A7 B7 V. Description of the invention (364) 1 ’Example 1 47 *

m/z 673 (M+H) 5 啻例 148*m / z 673 (M + H) 5 Example 148 *

(請先閱讀背面之注意事項再填寫本頁) m/z 759 (M+H) 經濟部中央標準局員工消費合作社印製 mο 1(Please read the notes on the back before filling this page) m / z 759 (M + H) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs mο 1

Η 十 (Μ 本紙張尺度適用中國國家標準（〇奶）八4規格（210'犬297公釐）_367 486469 A7 B7 五、發明説明（365 )Η Ten (Μ This paper size applies to Chinese national standard (0 milk) 8 4 specifications (210 'dog 297 mm) _367 486469 A7 B7 V. Description of the invention (365)

本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 368 - 486469 A7 B7 五、發明説明（366 )This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 368-486469 A7 B7 V. Description of invention (366)

m M- /fv 5m M- / fv 5

(請先閱讀背面之注意事項再填寫本頁) m(Please read the notes on the back before filling this page) m

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本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_ 369 - 486469 A7 B7 五、發明説明（367 ) 實例.156*This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 369-486469 A7 B7 V. Description of the invention (367) Example. 156 *

m/z 679 (M+H) 5 m/z 609 實例 1 ^1'm / z 679 (M + H) 5 m / z 609 Example 1 ^ 1 '

CM. (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印製 10 m/z 657 實例 153*CM. (Please read the notes on the back before filling this page) Order Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 10 m / z 657 Example 153 *

本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐37() 一 486469 A7 B7 五、發明説明（368 ) 啻例 1S9*This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm 37 (1) 486469 A7 B7 V. Description of the invention (368) Example 1S9 *

m/z 657 (M+H) (請先閲讀背面之注意事項再填寫本頁) 衣·m / z 657 (M + H) (Please read the precautions on the back before filling this page)

• 41T 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）_• 41T Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This paper size applies to China National Standard (CNS) A4 (210X297 mm) _

Claims (1)

27 27 τΛ Α8 Β8 C8 D8 、申請專利範圍 附件1 A : 第8 5 1 GG 9 7 8號專利申請案 中文申請專利範圍修正本 民國9 0年7月修正 物 合 化 之 構 結 列 下 有 具 一一a一 種 爲 Q 中 其 onnc (請先閱讀背面之注意事項再填寫本頁) 裝 R1爲下列結構之芴基型基團27 27 τΛ Α8 Β8 C8 D8, Annex 1 of the scope of patent application: A patent application No. 8 5 1 GG 9 7 8 Chinese application patent scope amendment The Republic of China July 1990 amendment structure composition is listed below One by one is its onnc in Q (please read the precautions on the back before filling this page). R1 is a fluorenyl group with the following structure. R 15 R' R 1爲下列結構之芘基型基團 :或者 經濟部智慧財產局員Η消費合作社印製 R13R 15 R 'R 1 is a basic group of the following structure: or printed by a consumer cooperative in the Intellectual Property Bureau of the Ministry of Economic Affairs R13 (a = 2,3 or 4) 或(a = 2, 3 or 4) or 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐’) 486469 Α8 R8 C8 _ 1)8 六、申請專利範圍 2 及22乃相同或互異，彼等乃各自爲一個鍵，S (〇)2 NH- C- II 〇 烷基 〇 •c_ It ο ， Η 或 —9— OH 惟有關I方面，21及22中至少有一者不爲一個鍵；R 爲Ci — 6烷撐或烯撐； R 12一 Z2 是 Ri2a一 N H — c = 0 或 一 C =〇 (請先閱讀背面之注意事項再填寫本頁) -烷基或多氟 其中R Ua是C 1-6 一烷基，氟一 C , — —烷基； z爲一個鍵，0或S ; R13，R14，R15，R15a，Rie 及 R16a 乃各自爲氫 或氛； 經濟部智慧財產局員工消費合作社印製 R5乃獨立爲Ci-6 —烷基，苯基，Ci-6 -烷氧基， 苯氧基’ C 3-6 -環烷基，環己基，吡啶基或噻吩基，且 上述基團均可經由可利用之碳原子而被1或2個選自氫， 鹵基’ CiM 一烷基，cf3，苯基，經鹵基取代之苯基， 經C F 3取代之苯基，甲氧基，吡啶基及苯並瞎唑基之基 團任意取代； R β爲氫；及 其製藥學上可接受之鹽類， 2 ·如申請專利範圍第1項之化合物，其具有下列化 學式 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -2 - 486469 A8 B8 C8 D8 ^jjpppl 申請專利範圍 R5 ο人 N. R1 I N 6 丨R 是 1 R 中 其 R RThis paper size applies to China National Standard (CNS) A4 (210 X 297 mm ') 486469 A8 R8 C8 _ 1) 8 6. The scope of patent applications 2 and 22 are the same or different, they are each a key, S (〇) 2 NH- C-II 〇alkyl 〇 • c_ It ο, Η or -9— OH But in the aspect of I, at least one of 21 and 22 is not a bond; R is Ci-6 alkylene or Alkenylene; R 12-Z2 is Ri2a-NH — c = 0 or -C = 0 (please read the notes on the back before filling out this page)-alkyl or polyfluoro where R Ua is C 1-6 monoalkyl , Fluoro-C, --- alkyl; z is a bond, 0 or S; R13, R14, R15, R15a, Rie and R16a are each hydrogen or atmosphere; R5 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is independent Ci-6-alkyl, phenyl, Ci-6-alkoxy, phenoxy 'C 3-6-cycloalkyl, cyclohexyl, pyridyl or thienyl, and all of the above groups are available through Carbon atom of which is selected from 1 or 2 hydrogen, halo 'CiM alkyl, cf3, phenyl, halo substituted phenyl, CF 3 substituted phenyl, methoxy, Pyridyl and benzazolyl groups are arbitrarily substituted; R β is hydrogen; and its pharmaceutically acceptable salts, 2 · If the compound in the scope of patent application No. 1 has the following chemical formula, this paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) -2-486469 A8 B8 C8 D8 ^ jjpppl Patent Application Range R5 ο Person N. R1 IN 6 丨 R is 1 R of which RR 物 合 化 之 項 第 圍 範 禾 專 請 串 如 3 爲 1 R 中 其Fan Hezhan, please refer to the item of compounding, such as 3 for 1 R 15 R1 4 R1 ------------裝--------訂--- (請先閱讀背面之注意事項再填寫本頁) Μ 物 合 化 之 項 3 第 圍 範 利 專 請 串 如 4 爲 1 R 中 其 線·_ 經濟部智慧財產局員工消費合作社印製15 R1 4 R1 ------------ Installation -------- Order --- (Please read the precautions on the back before filling in this page) Fan Li special please string as 4 is 1 R in the middle of the line · _ Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives 5 R1 4 R1 Η 氟 爲爲 自者 各 一 乃有 16中 R14 及 R ;15及 s R13 或 ，R 014且 ， R 者 鍵 ，一 個13有 一 R 中 爲16 z R 及 5 1 R 者 或 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱.) -3 一 486469 辛 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 Z1爲~個鍵或c =〇； R 11爲C 1 —6烷撐或C 2_6烯撐； 〇 R 1 2 — Z 2 爲 R12a — NH- c — ；或，r123 c — ； II 0 R12a爲Cp6烷基，氟化烷基或聚氟化〇1_6烷 基。 5 ·如申請專利範圍第1項之化合物，其具有下列結 構 R135 R1 4 R1 Η Fluorine is one of each and there are 16 of R14 and R; 15 and s R13 or, R 014 and R are bonds, and one of 13 has 16 R and 16 z R and 5 1 R or this Paper size applies to China National Standard (CNS) A4 specifications (210 X 297 public love.) -3 486469 Xin A8 B8 C8 D8 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6. The scope of patent application Z1 is ~ keys or c = 〇; R 11 is C 1-6 alkylene or C 2-6 olefin; 〇 R 1 2 — Z 2 is R12a — NH- c —; or r123 c —; II 0 R12a is Cp6 alkyl, fluorinated alkyl Radical or polyfluorinated 0_6 alkyl. 5 · If the compound in the scope of patent application No. 1 has the following structure R13 其中Q爲一c 一 ； Z爲一個鍵，0或S ; 其中R5乃獨立爲-烷基，苯基，—烷氧 基，苯氧基，C3_ β —環烷基，環己基，吡啶基或_吩基 ，且上述基團均可經由可利用之碳原子而被1或2個選自 氫，鹵基，Ci-4 一烷基，CF3，苯基，經鹵基取代之苯 基，經C F 3取代之苯基，甲氧基，吡啶基及苯並卩塞唑基 之基團任意取代； 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐·〉 (請先閱讀背面之注意事項再填寫本頁) 裝--------訂------- 486469 ' A8 • R8 C8 D8 、申請專利範圍 R 6 爲 Η ; R13及R15乃各自爲Η或F ; Ζ 1爲一個鍵； · R11爲Ci_e—院撐； 〇 R 12- Z 2爲C卜6—烷基— 或 C F 3—（ C ,-6)—烷基-nh4— ’ 或者Z2爲一個鍵且R12爲Ci_6 -烷基。 6 ·如申請專利範圍第5項之化合物，其中R11爲 一（CH2) 4—，Z1 爲一個鍵，且 R12— Z2 爲 (請先閱讀背面之注意事項再填寫本頁) -裝i ! uT* c OMC iH 經濟部智慧財產局員工消費合作社印製 7 ·如申請專利範圍第5項之化合物，其具有下列之 結構：Where Q is a c-; Z is a bond, 0 or S; where R5 is independently -alkyl, phenyl, -alkoxy, phenoxy, C3-β-cycloalkyl, cyclohexyl, pyridyl or _Phenyl, and the above-mentioned groups can be selected from hydrogen, halo, Ci-4 monoalkyl, CF3, phenyl, halo-substituted phenyl, via available carbon atoms, via CF 3 substituted phenyl, methoxy, pyridyl and benzopyrazolyl groups are arbitrarily substituted; This paper size applies to China National Standard (CNS) A4 (210 X 297 mm ·> (Please read first Note on the back, please fill out this page again.) -------- Order ------- 486469 'A8 • R8 C8 D8, the scope of patent application R 6 is Η; R13 and R15 are Η or F; Z 1 is a bond; R11 is Ci_e—institution; 〇R 12- Z 2 is C 6-alkyl— or CF 3— (C, -6) -alkyl-nh4— 'or Z2 is One bond and R12 is Ci_6-alkyl. 6 · For the compound in the scope of patent application item 5, where R11 is a (CH2) 4—, Z1 is a bond, and R12— Z2 is (Please read the precautions on the back first (Fill in this page again) -Install i! UT * c OMC iH Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 7 · If the compound in the scope of patent application No. 5 has the following structure: 且R12a爲三氟甲基一（Ci —β)—烷基或（Cpβ) —烷 基。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐·) 一 5 - 486469 A8 B8 C8 D8 六、申請專利範圍 8 .如申請專利範圍第1項之化合物，其具有下列之 結構 R13 R5&gt;CR12a is trifluoromethyl- (Ci —β) -alkyl or (Cpβ) -alkyl. This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm ·) 5-486469 A8 B8 C8 D8 6. Application for patent scope 8. If the compound in the scope of patent application No. 1 has the following structure R13 R5 &gt; C 其中Q爲 1〜； 〇 Z爲一個鍵，〇或s ; 其中R5乃獨立爲C i_6—院基，苯基，Ci-6 —院氧 基’苯氧基’ C 3-6 -環烷基，環己基，吡啶基或瞎吩基 ’且I:述基團均可經由可利用之碳原子而被丨或2個選自 氫’鹵基’ —烷基，CF3，苯基，經鹵基取代之苯 基’經C F 3取代之苯基，甲氧基，吡啶基及苯並卩塞唑基 之基團任意取代； R 6 爲 Η ; (請先閱讀背面之注意事項再填寫本頁) 裝--------訂---------線隊 經濟部智慧財產局員工消費合作社印製 R 一 C 及爲爲 3 1 111 R z R F 或 Η 爲 自 各 乃 5 1 撐 建烷 鍵 β 個1- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 6 486469 : A8 R8 C8 D8 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 R12 - Z2 爲 烷基一 I- ·或， II Ο c 1 - 6 - 院基一 C一 ， 或者Z 2爲一個鍵且R12爲Ci_6烷基。 9 ·如申請專利範圍第1項之化合物，其具有下列結構 X1Where Q is 1 ~; 〇Z is a bond, 〇 or s; where R5 is independently Ci_6—Cycloyl, phenyl, Ci-6—Cyclo-'phenoxy 'C 3-6-cycloalkyl , Cyclohexyl, pyridyl, or phenenyl 'and I: The groups can be selected via available carbon atoms or 2 selected from hydrogen' halo '-alkyl, CF3, phenyl, halo Substituted phenyl 'The phenyl, methoxy, pyridyl, and benzopyrazolyl groups substituted with CF 3 are arbitrarily substituted; R 6 is Η; (Please read the precautions on the back before filling this page) Equipment -------- Order --------- Line of the Ministry of Economic Affairs Intellectual Property Bureau Employees' Consumer Cooperatives printed R-C and 3 1 111 R z RF or Η is self-contained 5 1 Alkanes β β 1- This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 6 486469: A8 R8 C8 D8 -Z2 is alkyl-I- ·, or II oc 1-6-courtyard-C-, or Z 2 is a bond and R12 is Ci-6 alkyl. 9 · If the compound according to item 1 of the patent application has the following structure X1 包括其哌啶N —氧化物或其藥學上可接受之鹽，其中Z爲 一個鍵，0或S ; X1及X2乃各自爲Η或氟； Ζ是一鍵； X爲2至6之整數； R 爲吡啶基，瞎吩基，苯基或C 3_6 -環烷基，每 一個R55K基團被1或2個相同或互異之取代基所取代，該 取代基爲鹵素，吡啶基，苯並卩塞唑基，苯基，C I —烷基 ，Ci-e烷氧基，C3_e環烷基，經鹵基取代之苯基，或經 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ί清先閱讀背面之注意事項再填寫本頁) I裝--------訂--------- 一 Ί 一 486469 . A8 ' H8 C8 D8 經濟部智慧財產局員工消費合作社印製 /、、申睛專利範圍 C F 3取代之苯基。 1 0 ·如申請專利範圍第9項之化合物，其中Z爲一 個鍵，X1及X2各爲H。 1 1 ·如申請專利範圍第9項之化合物，其爲哌啶N 一氧化物。 1 2 ·如申請專利範圍第9項之化合物，其中， 〇 R5&quot;上之取代基乃鄰近於連結至1基團上之碳。 1 3 ·如申請專利範圍第9項之化合物，其中R5* 係被1或2個選自下列之基團所取代： I ，C 又，F ，C F 3 ,Including its piperidine N-oxide or a pharmaceutically acceptable salt thereof, wherein Z is a bond, 0 or S; X1 and X2 are each fluorene or fluorine; Z is a bond; X is an integer from 2 to 6; R is pyridyl, phenenyl, phenyl or C 3-6 -cycloalkyl, each R55K group is substituted with 1 or 2 identical or mutually different substituents, the substituents are halogen, pyridyl, benzo Pyridoxazolyl, phenyl, CI-alkyl, Ci-e alkoxy, C3-e cycloalkyl, halogen-substituted phenyl, or Chinese paper (CNS) A4 (210 X 297) Mm) ί Qing first read the notes on the back before filling out this page) I installed -------- order --------- Ί 486469. A8 'H8 C8 D8 Intellectual property of the Ministry of Economic Affairs Bureau employee consumer cooperatives printed /, and Shen Yan patent scope CF 3 substituted phenyl. 10 · For the compound in the ninth scope of the patent application, wherein Z is a bond and X1 and X2 are each H. 1 1. The compound according to item 9 of the scope of patent application, which is piperidine N monoxide. 1 2. The compound according to item 9 of the scope of patent application, wherein the substituent on 〇 R5 is adjacent to the carbon linked to the 1 group. 1 3. The compound according to item 9 of the scope of patent application, wherein R5 * is substituted by 1 or 2 groups selected from the group consisting of: I, C, F, C F 3, ------------裝--------訂--------- (請先閲讀背面之注意事項再填寫本頁) Ci-6烷基，苯基，被鹵基或CF3取代之苯基； 〇ch3;或環己基。 1 4 ·如申請專利範圍第1 3項之化合物， 其中（C Η 2) x爲（C Η 2) 4或 Ζ爲一個鍵； X 1及X 2各爲Η ; R5*爲苯基，其乃被三氟甲基苯基，苯並噻唑基，鹵 基及/或苯基所取代，或者 R 爲妣啶基或_吩基，其中r 包括連接至碳（此 本紙張尺度適用中國國家標準（CNS)A4規格（210 297公爱） 一 8 一 486469 A8 B8 C8 D8 六、申請專利範圍 碳乃鄰近於鍵結至C上之碳）上之取代基。 1 5 ·如申請專利範圍第1項之化合物，其具有下歹51 結構------------ Installation -------- Order --------- (Please read the notes on the back before filling this page) Ci-6 alkyl, Phenyl, phenyl substituted with halo or CF3; och3; or cyclohexyl. 14 · If the compound in the 13th scope of the patent application, (C Η 2) x is (C Η 2) 4 or Z is a bond; X 1 and X 2 are each Η; R5 * is phenyl, which It is substituted by trifluoromethylphenyl, benzothiazolyl, halo and / or phenyl, or R is pyridinyl or phenyl, where r includes a link to carbon (this paper size applies Chinese national standards (CNS) A4 specification (210 297 public love)-8-486469 A8 B8 C8 D8 VI. Patent application scope Carbon is adjacent to the carbon bonded to C) Substituent group. 1 5 · If the compound in the scope of patent application No. 1 has the following structure: N-CH2-CF3 a , ° ^=( (CH2 N-C- R5^ 包括其哌啶N-氧化物或其藥學上可接受之鹽， _ R 爲妣啶基、卩塞吩基、苯基或C 3 —β環烷基，每一 個R 5基團乃被1或2個相同或互異之取代基所取代，該 取代基爲鹵素，吡啶基，苯並_唑基，苯基，C 烷基 ，C^6烷氧基，C3_6環烷基，經鹵基取代之苯基，或經 C F 3取代之苯基。 1 6 .如申請專利範圍第1 5項之化合物，其中R 5 # ------------裝·-------訂·--------*^1^— (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 5 R 中 其 物 〇 合 碳化 之之 上項 團 5 基 1 OMMC 第 至圍 接範 I 達 禾 於專 近請 鄰申 乃如 基 · 代 7 取 1 之 上 爲被經鹵基取代之苯基所取代之苯基、或苯並噻唑基。 1 8 ·如申請專利範圍第1 7項之化合物，其中R 爲 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ' -9 - 486469 A8 B8 C8 -- _______ D8 六、申請專利範圍N-CH2-CF3 a, ° ^ = ((CH2 NC- R5 ^ includes piperidine N-oxide or a pharmaceutically acceptable salt thereof, _ R is pyrimidinyl, aceterenyl, phenyl or C 3-βcycloalkyl, each R 5 group is substituted by 1 or 2 identical or mutually different substituents, the substituents are halogen, pyridyl, benzo_azolyl, phenyl, C alkyl , C ^ 6 alkoxy, C3_6 cycloalkyl, phenyl substituted by halo, or phenyl substituted by CF 3. 16. The compound as claimed in item 15 of the scope of patent application, wherein R 5 #- ---------- Installation ------- Order · -------- * ^ 1 ^ — (Please read the precautions on the back before filling this page) Wisdom of the Ministry of Economy The property bureau employee consumer cooperative printed 5 R of its products, carbonized on top of the project group 5 base 1 OMMC first to enclose Fan I Dahe asked the neighbor Shen Nairuji on behalf of 7 to take 1 on top of being halogenated Phenyl substituted by phenyl substituted with phenyl, or benzothiazolyl. 1 8 · For the compounds in the 17th scope of the patent application, where R is the paper size and applicable Chinese National Standard (CNS) A4 (210 X 297) Mm) '-9-486469 A8 B8 C8-____ ___ D8 VI. Scope of patent application 1 9 ·如申請專利範圍第i 5項之化合物，其爲1 9 · If the compound in item i 5 of the scope of patent application is (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 2 0 · —種供預防、抑制或治療哺乳類動脈粥瘤硬化 或肥胖症之藥學組成物，其包含有效治療劑量之申請專利 範圍第1或9」項之化合物，及/或其藥學上可接受之載 劑。 2 1 · —種供降低血清脂肪濃度、膽固醇及/或三酸 甘油酯、或抑制及/或治療高脂血症、高脂肪血症、高脂 蛋白血症、高膽固醇血症、及/或高三酸甘油酯血症之醫 藥學組成物，其包含有效治療劑量之申請專利範圍第1或 9’項之化合物，及/或其藥學上可接受之載劑。 訂-------- .觀· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 一 10 -(Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 0 · —A pharmaceutical composition for the prevention, suppression or treatment of mammalian atherosclerosis or obesity, which contains effective A therapeutic dose of a compound in the scope of claims 1 or 9 ", and / or a pharmaceutically acceptable carrier thereof. 2 1 ·-for reducing serum fat concentration, cholesterol and / or triglycerides, or inhibiting and / or treating hyperlipidemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, and / or A pharmaceutical composition of hypertriglyceridemia, which comprises an effective therapeutic dose of a compound in the scope of claims 1 or 9 ', and / or a pharmaceutically acceptable carrier thereof. Order -------- .View · This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 1 10-
TW085100978A 1995-02-21 1996-01-26 Novel compounds for inhibiting microsomal triglyceride transfer protein and pharmaceutical compositions containing the same TW486469B (en)

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